1-pyrazolyl-3-(4-((2-anilinopyrimidin-4-yl) oxy) napththalen-1-yl) ureas as p38 MAP kinase inhibitors

ABSTRACT

There are provided compounds of formula (I) which are inhibitors of the family of p38 mitogen-activated protein kinase enzymes, and to their use in therapy, including in pharmaceutical combinations, especially in the treatment of inflammatory diseases, including inflammatory diseases of the lung, such as asthma and COPD.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/636,730, filed Jun. 29, 2017, which is a continuation of U.S. patentapplication Ser. No. 15/259,505, filed Sep. 8, 2016, which is acontinuation of U.S. patent application Ser. No. 14/349,356, filed Apr.3, 2014, which is the National Stage application under 35 U.S.C. 371 ofPCT International Application No. PCT/GB2012/052444, filed Oct. 3, 2012,which claims priority from European Patent Application No. EP11183688.8, filed Oct. 3, 2011, the contents of which are herebyincorporated by reference in their entirety.

FIELD OF THE INVENTION

The invention relates to compounds which are inhibitors of the family ofp38 mitogen-activated protein kinase enzymes (referred to herein as p38MAP kinase inhibitors), for example the alpha and gamma kinase sub-typesthereof, and to their use in therapy, including in pharmaceuticalcombinations, especially in the treatment of inflammatory diseases, inparticular inflammatory diseases of the lung, such as asthma and COPD,as well as those of the gastrointestinal tract, such as ulcerativecolitis and Crohn's disease and of the eye, such as uveitis.

BACKGROUND OF THE INVENTION

Four p38 MAPK isoforms (alpha, beta, gamma and delta respectively), havebeen identified each displaying different patterns of tissue expressionin man. The p38 MAPK alpha and beta isoforms are found ubiquitously inthe body, being present in many different cell types. The alpha isoformis well characterized in terms of its role in inflammation. Althoughstudies using a chemical genetic approach in mice indicate that the p38MAPK beta isoform does not play a role in inflammation (O'Keefe, S. J.et al., J. Biol. Chem., 2007, 282(48):34663-71.), it may be involved inpain mechanisms through the regulation of COX2 expression (Fitzsimmons,B. L. et al., Neuroreport, 2010, 21(4):313-7). These isoforms areinhibited by a number of previously described small molecular weightcompounds. Early classes of inhibitors were highly toxic due to thebroad tissue distribution of these isoforms which resulted in multipleoff-target effects of the compounds. Furthermore, development of asubstantial number of inhibitors has been discontinued due tounacceptable safety profiles in clinical studies (Pettus, L. H. andWurz, R. P., Curr. Top. Med. Chem., 2008, 8(16):1452-67.). As theseadverse effects vary with chemotype, and the compounds have distinctkinase selectivity patterns, the observed toxicities may bestructure-related rather than p38 mechanism-based.

Less is known about the p38 MAPK gamma and delta isoforms, which, unlikethe alpha and beta isozymes are expressed in specific tissues and cells.The p38 MAPK-delta isoform is expressed more highly in the pancreas,testes, lung, small intestine and the kidney. It is also abundant inmacrophages and detectable in neutrophils, CD4+ T cells and inendothelial cells (Shmueli, O. et al., Comptes Rendus Biologies, 2003,326(10-11):1067-1072; Smith, S. J. Br. J. Pharmacol., 2006, 149:393-404;Hale, K. K., J. Immunol., 1999, 162(7):4246-52; Wang, X. S. et al., J.Biol. Chem., 1997, 272(38):23668-23674.) Very little is known about thedistribution of p38 MAPK gamma although it is expressed more highly inbrain, skeletal muscle and heart, as well as in lymphocytes andmacrophages (Shmueli, O. et al., Comptes Rendus Biologies, 2003,326(10-11):1067-1072; Hale, K. K., J. Immunol., 1999, 162(7):4246-52;Court, N. W. et al., J. Mol. Cell. Cardiol., 2002, 34(4):413-26;Mertens, S. et al., FEBS Lett., 1996, 383(3):273-6.).

Selective small molecule inhibitors of p38 MAPK gamma and p38 MAPK deltaare not currently available, although one previously disclosed compound.BIRB 796, is known to possess pan-isoform inhibitory activity. Theinhibition of p38 MAPK gamma and delta isoforms is observed at higherconcentrations of the compound than those required to inhibit p38 MAPKalpha and p38 beta (Kuma, Y., J. Biol. Chem., 2005, 280:19472-19479.).In addition BIRB 796 also impaired the phosphorylation of p38 MAPKs orJNKs by the upstream kinase MKK6 or MKK4. Kuma discussed the possibilitythat the conformational change caused by the binding of the inhibitor tothe MAPK protein may affect the structure of both its phosphorylationsite and the docking site for the upstream activator, thereby impairingthe phosphorylation of p38 MAPKs or JNKs.

p38 MAP kinase is believed to play a pivotal role in many of thesignalling pathways that are involved in initiating and maintainingchronic, persistent inflammation in human disease, for example, insevere asthma and in COPD (Chung, F., Chest, 2011, 139(6):1470-1479.).There is now an abundant literature which demonstrates that p38 MAPkinase is activated by a range of pro-inflammatory cytokines and thatits activation results in the recruitment and release of additionalpro-inflammatory cytokines. Indeed, data from some clinical studiesdemonstrate beneficial changes in disease activity in patients duringtreatment with p38 MAP kinase inhibitors. For instance Smith describesthe inhibitory effect of p38 MAP kinase inhibitors on TNFα (but notIL-8) release from human PBMCs.

The use of inhibitors of p38 MAP kinase in the treatment of chronicobstructive pulmonary disease (COPD) has also been proposed. Smallmolecule inhibitors targeted to p38 MAPK α/β have proved to be effectivein reducing various parameters of inflammation in cells and in tissuesobtained from patients with COPD, who are generally corticosteroidinsensitive, (Smith, S. J., Br. J. Pharmacol., 2006, 149:393-404.) aswell as in various in vivo animal models (Underwood, D. C. et al., Am.J. Physiol., 2000, 279:L895-902; Nath, P. et al., Eur. J. Pharmacol.,2006, 544:160-167.). Irusen and colleagues have also suggested thepossible involvement of p38 MAPK α/β with corticosteroid insensitivityvia the reduction of binding affinity of the glucocorticoid receptor(GR) in nuclei (Irusen, E. et al., J. Allergy Clin. Immunol., 2002,109:649-657.). Clinical experience with a range of p38 MAP kinaseinhibitors, including AMG548, BIRB 796, VX702, SCIO469 and SCIO323 hasbeen described (Lee, M. R. and Dominguez, C., Current Med. Chem., 2005,12:2979-2994.).

COPD is a condition in which the underlying inflammation is reported tobe substantially resistant to the anti-inflammatory effects of inhaledcorticosteroids. Consequently, a superior strategy for treating COPDwould be to develop an intervention which has both inherentanti-inflammatory effects and the ability to increase the sensitivity ofthe lung tissues of COPD patients to inhaled corticosteroids. A recentpublication of Mercado (Mercado, N., et al., Mol. Pharmacol., 2011,80(6):1128-1135.) demonstrates that silencing p38 MAPK γ has thepotential to restore sensitivity to corticosteroids. Consequently theremay be a dual benefit for patients in the use of a p38 MAP kinaseinhibitor for the treatment of COPD and severe asthma. However, themajor obstacle hindering the utility of p38 MAP kinase inhibitors in thetreatment of human chronic inflammatory diseases has been the severetoxicity observed in patients resulting in the withdrawal from clinicaldevelopment of many compounds including all those specifically mentionedabove.

Many patients diagnosed with asthma or with COPD continue to suffer fromuncontrolled symptoms and from exacerbations of their medical conditionthat can result in hospitalisation. This occurs despite the use of themost advanced, currently available treatment regimens, comprising ofcombination products of an inhaled corticosteroid and a long actingβ-agonist. Data accumulated over the last decade indicates that afailure to manage effectively the underlying inflammatory component ofthe disease in the lung is the most likely reason that exacerbationsoccur. Given the established efficacy of corticosteroids asanti-inflammatory agents and, in particular, of inhaled corticosteroidsin the treatment of asthma, these findings have provoked intenseinvestigation. Resulting studies have identified that some environmentalinsults invoke corticosteroid-insensitive inflammatory changes inpatients' lungs. An example is the response arising fromvirally-mediated upper respiratory tract infections (URTI), which haveparticular significance in increasing morbidity associated with asthmaand COPD.

Epidemiological investigations have revealed a strong associationbetween viral infections of the upper respiratory tract and asubstantial percentage of the exacerbations suffered by patients alreadydiagnosed with chronic respiratory diseases. Some of the most compellingdata in this regard derives from longitudinal studies of childrensuffering from asthma (Papadopoulos, N. G., Papi, A., Psarras, S. andJohnston, S. L., Paediatr. Respir. Rev., 2004, 5(3):255-260.). A varietyof additional studies support the conclusion that a viral infection canprecipitate exacerbations and increase disease severity. For example,experimental clinical infections with rhinovirus have been reported tocause bronchial hyper-responsiveness to histamine in asthmatics that isunresponsive to treatment with corticosteroids (Grunberg, K., Sharon, R.F., et al., Am. J. Respir. Crit. Care Med., 2001, 164(10):1816-1822.).Further evidence derives from the association observed between diseaseexacerbations in patients with cystic fibrosis and HRV infections (Wat,D., Gelder, C., et al., J. Cyst. Fibros., 2008, 7:320-328.). Alsoconsistent with this body of data is the finding that respiratory viralinfections, including rhinovirus, represent an independent risk factorthat correlates negatively with the 12 month survival rate inpaediatric, lung transplant recipients (Liu, M., Worley, S., et al.,Transpl. Infect. Dis., 2009, 11(4):304-312.).

Clinical research indicates that the viral load is proportionate to theobserved symptoms and complications and, by implication, to the severityof inflammation. For example, following experimental rhinovirusinfection, lower respiratory tract symptoms and bronchialhyper-responsiveness correlated significantly with virus load (Message,S. D., Laza-Stanca, V., et al., PNAS, 2008; 105(36):13562-13567.).Similarly, in the absence of other viral agents, rhinovirus infectionswere commonly associated with lower respiratory tract infections andwheezing, when the viral load was high in immunocompetent paediatricpatients (Gerna, G., Piralla, A., et al., J. Med. Viral., 2009,81(8):1498-1507.).

Interestingly, it has been reported recently that prior exposure torhinovirus reduced the cytokine responses evoked by bacterial productsin human alveolar macrophages (Oliver, B. G., Lim, S., et al., Thorax,2008, 63:519-525.). Additionally, infection of nasal epithelial cellswith rhinovirus has been documented to promote the adhesion of bacteria,including S. aureus and H. influenzae (Wang, J. H., Kwon, H. J. andYong, J. J., The Laryngoscope, 2009, 119(7)1406-1411.). Such cellulareffects may contribute to the increased probability of patientssuffering a lower respiratory tract infection following an infection inthe upper respiratory tract. Accordingly, it is therapeutically relevantto focus on the ability of novel interventions to decrease viral load ina variety of in vitro systems, as a surrogate predictor of their benefitin a clinical setting.

High risk groups, for whom a rhinovirus infection in the upperrespiratory tract can lead to severe secondary complications, are notlimited to patients with chronic respiratory disease. They include, forexample, the immune compromised who are prone to lower respiratory tractinfection, as well as patients undergoing chemotherapy, who face acute,life-threatening fever. It has also been suggested that other chronicdiseases, such as diabetes, are associated with a compromisedimmuno-defence response. This increases both the likelihood of acquiringa respiratory tract infection and of being hospitalised as a result(Peleg, A. Y., Weerarathna, T., et al., Diabetes Metab. Res. Rev., 2007,23(1):3-13; Kornum, J. B., Reimar, W., et al., Diabetes Care, 2008,31(8):1541-1545.).

Whilst upper respiratory tract viral infections are a cause ofconsiderable morbidity and mortality in those patients with underlyingdisease or other risk factors; they also represent a significanthealthcare burden in the general population and are a major cause ofmissed days at school and lost time in the workplace (Rollinger, J. M.and Schmidtke, M., Med. Res. Rev., 2010, Doi 10.1002/med.20176.). Theseconsiderations make it clear that novel medicines, that possess improvedefficacy over current therapies, are urgently required to prevent andtreat rhinovirus-mediated upper respiratory tract infections. In generalthe strategies adopted for the discovery of improved antiviral agentshave targeted various proteins produced by the virus, as the point oftherapeutic intervention. However, the wide range of rhinovirusserotypes makes this a particularly challenging approach to pursue andmay explain why, at the present time, a medicine for the prophylaxis andtreatment of rhinovirus infections has yet to be approved by anyregulatory agency.

Viral entry into the host cell is associated with the activation of anumber of intracellular signalling pathways which are believed to play aprominent role in the initiation of inflammatory processes (reviewed byLudwig, S, 2007; Signal Transduction, 7:81-88.) and of viral propagationand subsequent release. One such mechanism, which has been determined toplay a role in influenza virus propagation in vitro, is activation ofthe phosphoinositide 3-kinase/Akt pathway. It has been reported thatthis signalling pathway is activated by the NS1 protein of the virus(Shin, Y. K., Liu, Q. et al., J. Gen. Virol., 2007, 88:13-18.) and thatits inhibition reduces the titres of progeny virus (Ehrhardt, C.,Marjuki, H. et al., Cell Microbiol., 2006, 8:1336-1348.).

Furthermore, the MEK inhibitor U0126 has been documented to inhibitviral propagation without eliciting the emergence of resistant variantsof the virus (Ludwig, S., Wolff, T. et al., FEBS Lett., 2004, 561(1-3):37-43.) More recently, studies targeting inhibition of Syk kinasehave demonstrated that the enzyme plays an important role in mediatingrhinovirus entry into cells and also virus-induced inflammatoryresponses, including ICAM-1 up-regulation (Sanderson, M. P., Lau, C. W.et al., Inflamm. Allergy Drug Targets, 2009, 8:87-95). Syk activity isreported to be controlled by c-Src as an upstream kinase in HRVinfection (Lau, C. et al., J. Immunol., 2008, 180(2):870-880.). A smallnumber of studies have appeared that link the activation of cellular Src(Src1 or p60-Src) or Src family kinases to infection with viruses. Theseinclude a report that adenovirus elicits a PI3 kinase mediatedactivation of Akt through a c-Src dependent mechanism. It has also beensuggested that Rhinovirus-39 induced IL-8 production in epithelial cellsdepends upon Src kinase activation (Bentley. J. K., Newcomb, D. C., J.Virol., 2007, 81:1186-1194.). Finally, it has been proposed thatactivation of Src kinase is involved in the induction of mucinproduction by rhinovirus-14 in epithelial cells and sub-mucosal glands(Inoue, D. and Yamaya, M., Respir. Physiol. Neurobiol., 2006,154(3):484-499.).

It has been disclosed previously that compounds that inhbit the activityof both c-Src and Syk kinases are effective agents against rhinovirusreplication (Charron, C. E. et al., WO 2011/158042.) and that compoundsthat inhibit p59-HCK are effective against influenza virus replication(Charron, C. E. et al., WO 2011/070369.). For the reasons summarisedabove, compounds designed to treat chronic respiratory diseases thatcombine these inherent properties with the inhibition of p38 MAPKs, areexpected to be particularly efficacious.

Certain p38 MAPK inhibitors have also been described as inhibitors ofthe replication of respiratory syncitial virus (Cass, L. et al., WO2011/158039.).

Furthermore, it is noteworthy that a p38 MAPK inhibitor was found todeliver benefit for patients with IBD after one week's treatment whichwas not sustained over a four week course of treatment (Schreiber, S. etal., Clin. Gastro. Hepatology, 2006, 4:325-334.).

In addition to playing key roles in cell signalling events which controlthe activity of pro-inflammatory pathways, kinase enzymes are now alsorecognised to regulate the activity of a range of cellular functions.Among those which have been discussed recently are the maintenance ofDNA integrity (Shilo, Y. Nature Reviews Cancer, 2003, 3:155-168.) andco-ordination of the complex processes of cell division. An illustrationof recent findings is a publication describing the impact of a set ofinhibitors acting upon the so-called “Olaharsky kinases” on thefrequency of micronucleus formation in vitro (Olaharsky, A. J. et al.,PLoS Comput. Biol., 2009, 5(7):e1000446.). Micronucleus formation isimplicated in, or associated with, disruption of mitotic processes andis therefore an undesirable manifestation of potential toxicity.Inhibition of glycogen synthase kinase 3α (GSK3α) was found to be aparticularly significant factor that increases the likelihood of akinase inhibitor promoting micronucleus formation. Recently, inhibitionof the kinase GSK3β with RNAi was also reported to promote micronucleusformation (Tighe, A. et al. BMC Cell Biology. 2007, 8:34.).

It may be possible to attenuate the adverse effects arising from druginteractions with Olaharsky kinases, such as GSK3α, by optimisation ofthe dose and/or by changing the route of administration. However, itwould be more advantageous to identify therapeutically useful moleculesthat demonstrate low or undectable activity against these off-targetenzymes and consequently elicit little or no disruption of mitoticprocesses, as measured in mitosis assays.

It is evident from consideration of the literature cited hereinabovethat there remains a need to identify and develop new p38 MAP kinaseinhibitors that have improved therapeutic potential over currentlyavailable treatments. Desirable compounds are those that exhibit asuperior therapeutic index by exerting, at the least, an equallyefficacious effect as previous agents but, in one or more respects, areless toxic at the relevant therapeutic dose. An objective of the presentinvention therefore, is to provide such novel compounds that inhibit theenzyme activity of p38 MAP kinase, for example with certain sub-typespecificities, together, preferably, with Syk kinase and tyrosinekinases within the Src family (particularly c-Src) thereby possessinggood anti-inflammatory properties, and suitable for use in therapy.

In one or more embodiments of the invention disclosed herein thecompounds of formula (I) exhibit a longer duration of action and/orpersistence of action in comparison to the previously disclosedallosteric p38 MAP kinase inhibitor BIRB 796 (Pargellis, C. et al.,Nature Struct. Biol., 2002, 9(4):268-272.).

SUMMARY OF THE INVENTION

Thus in one aspect of the invention there is provided a compound offormula (I):

wherein:

-   R¹ represents C₁₋₁₀ alkyl, C₃₋₁₀ cycloalkyl or halo substituted    C₁₋₁₀ alkyl,-   R² represents hydrogen, hydroxyl, halogen, C₁₋₆ alkyl or C₁₋₆    alkoxy,-   R³ represents phenyl optionally substituted by 1 to 3 substituents    independently selected from hydroxyl, halogen, C₁₋₆ alkyl and C₁₋₆    alkoxy,    or a pharmaceutically acceptable salt or solvate thereof, including    all stereoisomers and tautomers thereof.

DETAILED DESCRIPTION OF THE INVENTION

Alkyl as used herein refers to straight chain or branched chain alkyl,such as, without limitation, methyl, ethyl, n-propyl, iso-propyl, butyl,n-butyl and tert-butyl. In one embodiment alkyl refers to straight chainalkyl.

Alkoxy as used herein refers to straight or branched chain alkoxy, forexample methoxy, ethoxy, propoxy, butoxy. Alkoxy as employed herein alsoextends to embodiments in which the oxygen atom is located within thealkyl chain, for example —C₁₋₃ alkylOC₁₋₃ alkyl, such as —CH₂CH₂OCH₃ or—CH₂OCH₃. Thus in one embodiment the alkoxy is linked through carbon tothe remainder of the molecule. In one embodiment the alkoxy is linkedthrough oxygen to the remainder of the molecule, for example —OC₁₋₆alkyl. In one embodiment the disclosure relates to straight chainalkoxy.

Halogen includes fluoro, chloro, bromo or iodo, in particular fluoro,chloro or bromo, especially fluoro or chloro.

Alkyl substituted by halo as employed herein refers to alkyl groupshaving 1 to 6 halogen atoms, for example 1 to 5 halogens, such as perhaloalkyl, in particular perfluoroalkyl, more specifically —CF₂CF₃ orCF₃.

C₁₋₁₀ alkyl includes C₂, C₃, C₄, C₅, C₆, C₇, C₈ or C₉ as well as C₁ andC₁₀.

In one embodiment R¹ is t-butyl.

In one embodiment R² represents a meta or para substituent, especially apara substituent.

In one embodiment R² represents hydrogen, methyl, methoxy or hydroxyl,for example methyl or methoxy, such as methyl.

In one embodiment R³ represents unsubstituted phenyl.

In one embodiment R³ represents phenyl bearing one to three substituentsindependently selected from methyl, ethyl, isopropyl, hydroxyl, methoxy,ethoxy, fluoro or chloro, such as independently selected from methyl,hydroxyl, methoxy or chloro.

In one embodiment the phenyl of R³ bears one substituent. The selectedsubstituent may for example be located in the 2, 3 or 4 position such asthe 3 or 4 position, e.g. the 4 position.

In one embodiment the phenyl of R³ bears two substituents, for examplelocated in the 3, 4 position. In another embodiment the two substituentsmay be located in the 2,4 position. In another embodiment the twosubstituents may be located in the 2,5 position.

Examples of disubstituted phenyl include 2,4-dimethoxy, 2,5-dimethyl,2-methyl-4-chloro, 2-methyl-4-hydroxyl, 3-methoxy-4-hydroxyl,3-hydroxyl-4-methyl, 3,4-dimethoxy, 3-chloro-4-methoxy,3-fluoro-4-hydroxyl, 2-fluoro-4-hydroxyl, 2-chloro-4-hydroxyl and2,4-dihydroxyl.

In one embodiment, the phenyl of R³ either has hydrogen in the paraposition or when it bears a substituent in the para position saidsubstituent is selected from methyl, hydroxyl, methoxy, fluoro orchloro.

Exemplary compounds of formula (I) are selected from the groupconsisting of:

-   1-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-(2-(phenylamino)pyrimidin-4-yloxy)naphthalen-1-yl)urea;-   1-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((3-hydroxyphenyl)    amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(4-hydroxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2-(phenylamino)    pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((2-fluorophenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((2-methoxyphenyl)amino)    pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((2-chlorophenyl)amino)    pyrimidin-4-yl)oxy)naphthalen-1-yl)urea:-   1-(3-(tert-butyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2-(phenylamino)    pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((2,4-dimethoxyphenyl)amino)    pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((4-hydroxyphenyl)amino)    pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((2,5-dimethylphenyl)amino)    pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-(p-tolylamino)pyrimidin-4-yl)oxy)    naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-(m-tolylamino)pyrimidin-4-yl)oxy)    naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((3-chlorophenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((3-methoxyphenyl)amino)    pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((3-fluorophenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((4-chlorophenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((4-methoxyphenyl)amino)    pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((4-chloro-2-methylphenyl)amino)    pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((2-chlorophenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((2-isopropylphenyl)amino)    pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-(o-tolylamino)pyrimidin-4-yl)oxy)    naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((4-ethoxyphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((4-fluorophenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((4-hydroxy-2-methylphenyl)    amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((4-hydroxy-3-methoxyphenyl)    amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((3-hydroxy-4-methylphenyl)    amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((3,4-dimethoxyphenyl)amino)    pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((3-chloro-4-methoxyphenyl)    amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((3-fluoro-4-hydroxyphenyl)amino)    pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((2-fluoro-4-hydroxyphenyl)amino)    pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((2-chloro-4-hydroxyphenyl)    amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((2,4-dihydroxyphenyl)amino)    pyrimidin-4-yl)oxy)naphthalen-1-yl)urea; and-   1-(3-(tert-butyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((4-hydroxyphenyl)    amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;    and pharmaceutically acceptable salts and solvate of any one    thereof, including all stereoisomers and tautomers thereof.

Examples of salts of compounds of formula (I) include allpharmaceutically acceptable salts, such as, without limitation, acidaddition salts of strong mineral acids such as HCl and HBr salts andaddition salts of strong organic acids such as methanesulfonic acid.

As employed herein below the definition of a compound of formula (I) isintended to include salts, solvates, and all tautomers of said compound,unless the context specifically indicates otherwise. Examples ofsolvates include hydrates.

The invention provided herein extends to prodrugs of the compound offormula (I), that is to say compounds which break down and/or aremetabolised in vivo to provide an active compound of formula (I).General examples of prodrugs include simple esters, and other esterssuch as mixed carbonate esters, carbamates, glycosides, ethers, acetalsand ketals.

In a further aspect of the invention there is provided one or moremetabolites of the compound of formula (I), in particular a metabolitethat retains one or more of the therapeutic activities of the compoundof formula (I). A metabolite, as employed herein, is a compound that isproduced in vivo from the metabolism of the compound of formula (I),such as, without limitation, oxidative metabolites and/or metabolitesgenerated, for example, from O-dealkylation.

The compounds of the disclosure include those where the atom specifiedis a naturally occurring or non-naturally occurring isotope. In oneembodiment the isotope is a stable isotope. Thus the compounds of thedisclosure include, for example deuterium containing compounds and thelike.

The disclosure also extends to all polymorphic forms of the compoundsherein defined.

Two generic routes by which compound examples of the invention may beconveniently prepared are summarised below (Scheme 1).

Thus compounds of formula (I) may be obtained by a general process,Route A, whereby a naphthylamine precusor represented by Intermediate Bis coupled with an activated, electrophilic derivative represented byIntermediate A* prepared from the corresponding amine precursorIntermediate A (X═H). The fragment LG₁ in Intermediate A* is a suitableleaving group such as an imidazoyl (C₃H₃N₂) or a phenoxy (C₆H₅O)radical.

In the first case the electrophilic compounds, intermediate A* areobtained by reaction of the corresponding amine with CDI in a non polaraprotic solvent, such as DCM and are conveniently generated in situ atRT and then reacted without isolation with compounds represented byIntermediate B. In the second case the required activated aminecomponents may be generated by treatment of the amine precursors with asuitable chloroformate, such as, for example, phenyl chloroformate, inthe presence of a base. The activation process is conveniently carriedout under Schotten Baumann type conditions, that is using an aqueousbase, such as aq sodium carbonate and under biphasic conditions. Theactivated amine derivatives represented by intermediate A, wherein LG₁is a aryloxy, for example phenoxy, may also be generated optionally insitu and then reacted without isolation with compounds represented byIntermediate B to provide compound examples of formula (I).

In addition, compounds of the invention may be generated by analternative synthetic process Route B, employing a displacement reactionbetween an appropriate amine (R³NH₂) and a pyrimidine compoundrepresented by intermediate C in which LG₂ is a suitable leaving groupsuch as a halogen, for example, a chlorine atom. The reaction proceedsunder acidic conditions, in a suitable organic solvent for example inthe presence of p-TSA and in THF.

Compounds represented by Intermediate B and Intermediate C may beobtained using the same two transformative processes described hereinabove starting from compounds represented by Intermediate D (Scheme 2).

The common precursors represented by Intermediate D are, in turn,readily prepared by a regioselective S_(N)Ar displacement reactionbetween a suitably functionalised pyrimidine and 4-aminonaphthalen-1-ol,in which LG₃ is leaving group, such as a halogen atom, for examplechlorine. The reaction is conveniently carried out in the presence of abase such as triethylamine and in a non polar, aprotic solvent such asdicloromethane. The pyrimidine starting materials are eithercommercially available or are readily prepared by synthetic protocolsthat are well established in the art.

Protective groups may be required to protect chemically sensitive groupsduring one or more of the reactions described above, to ensure that theprocess can be carried out and/or is efficient. Thus if desired ornecessary, intermediate compounds may be protected by the use ofconventional protective groups. Protective groups and the means fortheir removal are described in “Protective Groups in Organic Synthesis”,by Theodora W. Greene and Peter G. M. Wuts, published by John Wiley &Sons Inc; 4th Rev Ed., 2006, ISBN-10: 0471697540.

Novel intermediates as described herein form an aspect of the invention.

The compounds of formula (I) are p38 MAP kinase inhibitors (especiallyof the alpha subtype) and in one aspect the compounds are useful in thetreatment of inflammatory diseases, for example COPD and/or asthma.

In one embodiment the compounds of formula (I) do not strongly inhibitGSK 3α, for example they have an IC₅₀ against GSK 3α of 1500 nM orgreater; such as 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000or 10,000 nM or greater.

Persistence of action as used herein is related to the dissociation rateor dissociation constant of the compound from the target (such as areceptor). A low dissociation rate may lead to persistence.

A low dissociation rate in combination with a high association ratetends to provide potent therapeutic entities.

The compounds of formula (I) are expected to be potent in vivo.

Typically, the prior art compounds developed to date have been intendedfor oral administration. This strategy involves optimizing compoundswhich achieve their duration of action by an appropriate pharmacokineticprofile. This ensures that a sufficiently high drug concentration isestablished and maintained between doses to provide clinical benefit.The inevitable consequence of this approach is that all bodily tissues,and especially the liver and the gut, are likely to be exposed tosupra-therapeutically active concentrations of the drug, whether or notthey are adversely affected by the disease being treated.

An alternative strategy is to design treatment paradigms in which thedrug is dosed directly to the inflamed organ (topical therapy). Whilethis approach is not suitable for treating all chronic inflammatorydiseases, it has been extensively exploited in lung diseases (asthma,COPD), skin diseases (atopic dermatitis and psoriasis), nasal diseases(allergic rhinitis) and gastrointestinal diseases (ulcerative colitis).

In topical therapy, efficacy can be achieved either by (i) ensuring thatthe drug has a sustained duration of action and is retained in therelevant organ to minimize the risks of systemic toxicity or (ii)producing a formulation which generates a “reservoir” of the active drugwhich is available to sustain the drug's desired effects. Approach (i)is exemplified by the anticholinergic drug tiotropium (Spiriva), whichis administered topically to the lung as a treatment for COPD, and whichhas an exceptionally high affinity for its target receptor, resulting ina very slow off rate and a consequent sustained duration of action.

In one aspect of the disclosure the compound of formula (I) isparticularly suitable for topical delivery, such as topical delivery tothe lungs, in particular for the treatment of respiratory disease, forexample chronic respiratory diseases such as COPD and/or asthma.

In one embodiment the compound of formula (I) is suitable forsensitizing patients to treatment with a corticosteroid who have becomerefractory to such treatment regimens.

The compound of formula (I) may also be useful for the treatment ofrheumatoid arthritis.

The compound of formula (I) may have antiviral properties, for examplethe ability to prevent infection of cells (such as respiratoryepithelial cells) with a picornavirus, in particular a rhinovirus,influenza or respiratory synctial virus.

Thus the compound is thought to be an antiviral agent, in particularsuitable for the prevention, treatment or amelioration of picornavirusinfections, such as rhinovirus infection, influenza or respiratorysyncitial virus.

In one embodiment the compound of formula (I) is able to reduceinflammation induced by viral infection, such as rhinovirus infectionand in particular viral infections that result in the release ofcytokines such as IL-8, especially in viva This activity may, forexample, be tested in vitro employing a rhinovirus induced IL-8 assay asdescribed in the Examples herein.

In one embodiment the compound of formula (I) is able to reduce ICAM1expression induced by rhinovirus, especially in vivo. ICAM1 is thereceptor mechanism used by so-called major groove rhinovirus serotypesto infect cells. This activity may be measured, for example by a methoddescribed in the Examples herein.

It is expected that the above properties render the compound of formula(I) particularly suitable for use in the treatment and/or prophylaxis ofexacerbations of inflammatory diseases, in particular viralexacerbations, in patients with one or more of the following chronicconditions such as congestive heart failure, COPD, asthma, diabetes,cancer and/or in immunosuppressed patients, for example post-organtransplant.

In particular, the compound of formula (I) may be useful in thetreatment of one or more respiratory disorders including COPD (includingchronic bronchitis and emphysema), asthma, paediatric asthma, cysticfibrosis, sarcoidosis, idiopathic pulmonary fibrosis, allergic rhinitis,rhinitis, sinusitis, especially asthma, and COPD (including chronicbronchitis and emphysema).

The compound of formula (I) may also be useful in the treatment of oneor more conditions which may be treated by topical or local therapyincluding allergic conjunctivitis, conjunctivitis, allergic dermatitis,contact dermatitis, psoriasis, ulcerative colitis, inflamed jointssecondary to rheumatoid arthritis or to osteoarthritis.

It is also expected that the compound of formula (I) may be useful inthe treatment of certain other conditions including rheumatoidarthritis, pancreatitis, cachexia, inhibition of the growth andmetastasis of tumours including non-small cell lung carcinoma, breastcarcinoma, gastric carcinoma, colorectal carcinomas and malignantmelanoma.

The compound of formula (I) may be useful in the treatment of eyediseases or disorders including allergic conjunctivitis, conjunctivitis,diabetic retinopathy, macular oedema (including wet macular oedema anddry macular oedema), post-operative cataract inflammation or,particularly, uveitis (including posterior, anterior and pan uveitis).

The compound of formula (I) may be useful in the treatment ofgastrointestinal diseases or disorders including ulcerative colitis orCrohn's disease.

The compound of formula (I) may also re-sensitise the patient'scondition to treatment with a corticosteroid, when the patient'scondition has become refractory to the same.

Furthermore, the present invention provides a pharmaceutical compositioncomprising a compound according to the disclosure optionally incombination with one or more pharmaceutically acceptable diluents orcarriers.

Diluents and carriers may include those suitable for parenteral, oral,topical, mucosal and rectal administration.

As mentioned above, such compositions may be prepared e.g. forparenteral, subcutaneous, intramuscular, intravenous, intra-articular orperi-articular administration, particularly in the form of liquidsolutions or suspensions; for oral administration, particularly in theform of tablets or capsules; for topical e.g. pulmonary or intranasaladministration, particularly in the form of powders, nasal drops oraerosols and transdermal administration; for mucosal administration e.g.to buccal, sublingual or vaginal mucosa, and for rectal administratione.g. in the form of a suppository.

The compositions may conveniently be administered in unit dosage formand may be prepared by any of the methods well-known in thepharmaceutical art, for example as described in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,(1985). Formulations for parenteral administration may contain asexcipients sterile water or saline, alkylene glycols such as propyleneglycol, polyalkylene glycols such as polyethylene glycol, oils ofvegetable origin, hydrogenated naphthalenes and the like. Formulationsfor nasal administration may be solid and may contain excipients, forexample, lactose or dextran, or may be aqueous or oily solutions for usein the form of nasal drops or metered sprays. For buccal administrationtypical excipients include sugars, calcium stearate, magnesium stearate,pregelatinated starch, and the like.

Compositions suitable for oral administration may comprise one or morephysiologically compatible carriers and/or excipients and may be insolid or liquid form. Tablets and capsules may be prepared with bindingagents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, orpoly-vinylpyrollidone; fillers, such as lactose, sucrose, corn starch,calcium phosphate, sorbitol, or glycine; lubricants, such as magnesiumstearate, talc, polyethylene glycol, or silica; and surfactants, such assodium lauryl sulfate. Liquid compositions may contain conventionaladditives such as suspending agents, for example sorbitol syrup, methylcellulose, sugar syrup, gelatin, carboxymethyl-cellulose, or ediblefats; emulsifying agents such as lecithin, or acacia; vegetable oilssuch as almond oil, coconut oil, cod liver oil, or peanut oil;preservatives such as butylated hydroxyanisole (BHA) and butylatedhydroxytoluene (BHT). Liquid compositions may be encapsulated in, forexample, gelatin to provide a unit dosage form.

Solid oral dosage forms include tablets, two-piece hard shell capsulesand soft elastic gelatin (SEG) capsules.

A dry shell formulation typically comprises of about 40% to 60% w/wconcentration of gelatin, about a 20% to 30% concentration ofplasticizer (such as glycerin, sorbitol or propylene glycol) and about a30% to 40% concentration of water. Other materials such aspreservatives, dyes, opacifiers and flavours also may be present. Theliquid fill material comprises a solid drug that has been dissolved,solubilized or dispersed (with suspending agents such as beeswax,hydrogenated castor oil or polyethylene glycol 4000) or a liquid drug invehicles or combinations of vehicles such as mineral oil, vegetableoils, triglycerides, glycols, polyols and surface-active agents.

Suitably a compound of formula (I) is administered topically to thelung. Hence we provide according to the invention a pharmaceuticalcomposition comprising a compound of the disclosure optionally incombination with one or more topically acceptable diluents or carriers.Topical administration to the lung may be achieved by use of an aerosolformulation. Aerosol formulations typically comprise the activeingredient suspended or dissolved in a suitable aerosol propellant, suchas a chlorofluorocarbon (CFC) or a hydrofluorocarbon (HFC). Suitable CFCpropellants include trichloromonofluoromethane (propellant 11),dichlorotetrafluoro methane (propellant 114), anddichlorodifluoromethane (propellant 12). Suitable HFC propellantsinclude tetrafluoroethane (HFC-134a) and heptafluoropropane (HFC-227).The propellant typically comprises 40% to 99.5% e.g. 40% to 90% byweight of the total inhalation composition. The formulation may compriseexcipients including co-solvents (e.g. ethanol) and surfactants (e.g,lecithin, sorbitan trioleate and the like). Aerosol formulations arepackaged in canisters and a suitable dose is delivered by means of ametering valve (e.g. as supplied by Bespak, Valois or 3M).

Topical administration to the lung may also be achieved by use of anon-pressurised formulation such as an aqueous solution or suspension.This may be administered by means of a nebuliser. Topical administrationto the lung may also be achieved by use of a dry-powder formulation. Adry powder formulation will contain the compound of the disclosure infinely divided form, typically with a mass mean aerodynamic diameter(MMAD) of 1-10 μm. The formulation will typically contain a topicallyacceptable diluent such as lactose, usually of large particle size e.g.an MMAD of 100 μm or more. Examples of dry powder delivery systemsinclude SPINHALER, DISKHALER, TURBOHALER, DISKUS and CLICKHALER. Acompound of formula (I) has therapeutic activity. In a further aspect,the present invention provides a compound of the disclosure for use as amedicament. Thus, in a further aspect, the present invention provides acompound as described herein for use in the treatment of one or more ofthe above mentioned conditions.

In a further aspect, the present invention provides use of a compound asdescribed herein for the manufacture of a medicament for the treatmentof one or more of the above mentioned conditions.

In a further aspect, the present invention provides a method oftreatment of one or more of the above mentioned conditions whichcomprises administering to a subject an effective amount of a compoundof the disclosure or a pharmaceutical composition comprising thecompound.

The word “treatment” is intended to embrace prophylaxis as well astherapeutic treatment.

A compound of the disclosure may also be administered in combinationwith one or more other active ingredients e.g. active ingredientssuitable for treating the above mentioned conditions. For examplepossible combinations for treatment of respiratory disorders includecombinations with steroids (e.g. budesonide, beclomethasonedipropionate, fluticasone propionate, mometasone furoate, fluticasonefuroate), beta agonists (e.g. terbutaline, salbutamol, salmeterol,formoterol) and/or xanthines (e.g. theophylline). Other suitable activesinclude anticholinergics, such as tiotropium and anti-viral agents suchas, but not limited to, zanamivir or oseltamivir, for example as thephosphate. Other anti-viral agents include peramivir and laninamivir.

The data generated below in relation to the antiviral properties of thecompounds of formula (I) leads the inventors to believe that otherantiviral therapies would be useful in the treatment or prevention ofexacerbations suffered by patients with respiratory disease such as COPDand/or asthma and/or one or more of the indications listed above. Thusin one aspect there is provided the use of an anti-viral therapy, suchas, but not limited to, zanamavir or oseltamivir (for exampleoseltamivir phosphate), in the treatment or prevention of respiratoryviral infections in patients with chronic conditions such as congestiveheart failure, diabetes, cancer, or in immunosuppressed patients, forexample post-organ transplant.

EXPERIMENTAL SECTION

Abbreviations used herein are defined below (Table 1). Any abbreviationsnot defined are intended to convey their generally accepted meaning.

TABLE 1 Abbreviations AcOH glacial acetic acid aq aqueous ATPadenosine-5′-triphosphate BALF bronchoalveolae lavage fluid br broad BSAbovine serum albumin CatCart ® catalytic cartridge CDI1,1-carbonyl-diimidazole COPD chronic obstructive pulmonary disease ddoublet DCM dichloromethane DMSO dimethyl sulfoxide d-U937 cells PMAdifferentiated U-937 cells (ES⁺) electrospray ionization, positive modeEt ethyl EtOAc ethyl acetate FCS foetal calf serum FRET fluorescenceresonance energy transfer GSK3α glycogen synthase kinase 3α HBEC primaryhuman bronchial epithelial cells hr hour(s) HRP horseradish peroxidiseHRV human rhinovirus ICAM-1 inter-cellular adhesion molecule 1 JNK c-JunN-terminal kinase LPS lipopolysaccharide (M + H)⁺ protonated molecularion MAPK mitogen protein activated protein kinase MAPKAP-K2mitogen-activated protein kinase-activated protein kinase-2 Me methylMeCN acetonitrile MeOH methanol MHz megahertz MMAD mass medianaerodynamic diameter MOI multiplicity of infection min minute(s) MTT3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide m/z:mass-to-charge ratio NMR nuclear magnetic resonance (spectroscopy) PBMCperipheral blood mononuclear cell PBS phosphate buffered saline Phphenyl PHA phytohaemagglutinin PMA phorbol myristate acetate pTSA4-methylbenzenesulfonic acid q quartet RT room temperature RP HPLCreverse phase high performance liquid chromatography RSV respiratorysyncytical virus s singlet sat saturated SCX solid supported cationexchange (resin) SDS sodium dodecyl sulphate S_(N)Ar nucleophilicaromatic substitution t triplet TBDMS tert-butyldimethylsilyl TCID₅₀ 50%tissue culture infectious dose THF tetrahydrofuran TNFα tumor necrosisfactor alphaGeneral Procedures

All starting materials and solvents were obtained either from commercialsources or prepared according to the literature citation. Unlessotherwise stated all reactions were stirred. Organic solutions wereroutinely dried over anhydrous magnesium sulfate. Hydrogenations wereperformed on a Thales H-cube flow reactor under the conditions stated.

Column chromatography was performed on pre-packed silica (230-400 mesh,40-63 μm) cartridges using the amount indicated. SCX was purchased fromSupelco and treated with 1M hydrochloric acid prior to use. Unlessstated otherwise the reaction mixture to be purified was first dilutedwith MeOH and made acidic with a few drops of AcOH. This solution wasloaded directly onto the SCX and washed with MeOH. The desired materialwas then eluted by washing with 1% NH₃ in MeOH.

Preparative Reverse Phase High Performance Liquid Chromatography:Agilent Scalar column C18, 5 μm (21.2×50 mm), flow rate 28 mL min⁻¹eluting with a H₂O-MeCN gradient containing 0.1% v/v formic acid over 10min using UV detection at 215 and 254 nm. Gradient information: 0.0-0.5min; 95% H₂O-5% MeCN; 0.5-7.0 min; ramped from 95% H₂O-5% MeCN to 5%H₂O-95% MeCN; 7.0-7.9 min; held at 5% H₂O-95% MeCN; 7.9-8.0 min;returned to 95% H₂O-5% MeCN; 8.0-10.0 min; held at 95% H₂O-5% MeCN.

Analytical Methods

Reverse Phase High Performance Liquid Chromatography: (Method 1):Agilent Scalar column C18, 5 μm (4.6×50 mm) or Waters XBridge C18, 5 μm(4.6×50 mm) flow rate 2.5 mL min⁻¹ eluting with a H₂O-MeCN gradientcontaining either 0.1% v/v formic acid (Method 1 acidic) or NH₃ (Method1 basic) over 7 min employing UV detection at 215 and 254 nm. Gradientinformation: 0.0-0.1 min, 95% H₂O-5% MeCN: 0.1-5.0 min, ramped from 95%H₂O-5% MeCN to 5% H₂O-95% MeCN: 5.0-5.5 min, held at 5% H₂O-95% MeCN;5.5-5.6 min, held at 5% H₂O-95% MeCN, flow rate increased to 3.5 mLmin⁻¹; 5.6-6.6 min, held at 5% H₂O-95% MeCN, flow rate 3.5 mL min⁻¹;6.6-6.75 min, returned to 95% H₂O-5% MeCN, flow rate 3.5 mL min⁻¹;6.75-6.9 min, held at 95% H₂O-5% MeCN, flow rate 3.5 mL min⁻¹; 6.9-7.0min, held at 95% H₂O-5% MeCN, flow rate reduced to 2.5 mL min⁻¹.

Reverse Phase High Performance Liquid Chromatography: Method 2: AgilentExtend C18 column, 1.8 μm (4.6×30 mm) at 40° C.; flow rate 2.5-4.5 mLmin⁻¹ eluting with a H₂O-MeCN gradient containing 0.1% v/v formic acidover 4 min employing UV detection at 254 nm. Gradient information:0-3.00 min, ramped from 95% H₂O-5% MeCN to 5% H₂O-95% MeCN; 3.00-3.01min, held at 5% H₂O-95% MeCN, flow rate increased to 4.5 mL min⁻¹; 3.013.50 min, held at 5% H₂O-95% MeCN; 3.50-3.60 min, returned to 95% H₂O-5%MeCN, flow rate reduced to 3.50 mL min⁻¹; 3.60-3.90 min, held at 95%H₂O-5% MeCN; 3.90-4.00 min, held at 95% H₂O-5% MeCN, flow rate reducedto 2.5 mL min⁻¹.

¹H NMR Spectroscopy: ¹H NMR spectra were acquired on a Bruker Avance IIIspectrometer at 400 MHz using residual undeuterated solvent as referenceand unless specified otherwise were run in DMSO-d₆.

The following intermediates used to prepare Compound (I) of theinvention have been previously described and were prepared using theprocedures contained in the references cited below (Table 2).

TABLE 2 Previously Described Intermediates. Intermediate Structure Name,LCMS Data and Reference A1

3-tert-butyl-1-p-tolyl-1H-pyrazol-5-amine. R^(t) 2.46 min (Method 1basic); m/z 230 (M + H)⁺, (ES⁺). Cirillo, P. F. et al., WO 2000/43384,27 Jul 2000. A2

3-tert-butyl-1-(4-ethoxyphenyl)-1H-pyrazol-5- amine. R^(t) 1.32 min(Method 2); m/z 246 (M + H)⁺, (ES⁺). Mathias, J. P. et al., US2006/0035922, 10 Aug 2005. A3

3-tert-butyl-1-(4-(tert-butyldimethylsilyloxy)phenyl)-1H-pyrazol-5-amine. R^(t) 2.80 min (Method 2); m/z 346 (M + H)⁺, (ES⁺).Mathias, J. P. et al., US 2006/0035922, 10 Aug 2005. D1

4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-amine. R^(t) 1.80 min(Method 2); m/z 272/274 (M + H)⁺, (ES⁺). Cirillo, P. F. et al., WO2002/92576, 21 Nov 2000.

Intermediate B14-((4-Aminonaphthalen-1-yl)oxy)-N-phenylpyrimidin-2-amine.

To a nitrogen purged solution of mixture of Intermediate D1 (50.0 g, 184mmol) and aniline (42.0 mL, 460 mmol) in THF (200 mL) was added pTSA(17.5 g, 92.0 mmol) in a single portion. The reaction mixture was heatedto 70° C. for 1.5 hr during which time which a precipitate formed. Themixture was cooled to RT and diluted with THF (200 mL). The precipitatewas collected by filtration, washed with THF (2×100 mL) and thensuspended in a heterogeneous mixture of DCM (600 mL) and aq. NaOH (2M,200 mL) and stirred vigorously for 1 hr, during which time the suspendedsolids dissolved. The layers were separated and the aq layer wasextracted with DCM (200 mL). The DCM extracts were combined, dried andevaporated in vacua The residue was triturated with ether (150 mL) andthe resulting solid was washed with ether (2×50 mL) to affordIntermediate B1 as an off white solid (26 g, 43%); R^(t) 1.95 min(Method 2); m/z 329 (M+H)⁺ (ES⁺).

Intermediate C11-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-yl)urea.

To a suspension of CDI (4.81 g, 29.7 mmol) in DCM (60 mL) was addedIntermediate A1 (8.50 g, 29.7 mmol) portion-wise. After 3 hr an aliquotof this solution containing the activated CDI adduct, (30 mL, 15 mmol)was added to a solution of Intermediate D1 (3.01 g, 9.97 mmol) in DCM(60 mL) and the reaction mixture maintained at RT. After 2 hr a secondaliquot of the CDI adduct solution (6.0 mL, 6.0 mmol) was added and thereaction mixture kept at RT for a further 16 hr. The resulting mixturewas diluted with DCM (100 mL) and washed with saturated aq. NaHCO₃ (100mL) and water (2×100 mLl) and then dried and evaporated in vacuo. Theresidue was purified by flash column chromatography (SiO₂, [10% MeOH inDCM] in DCM, 0-100%, gradient elution then SiO₂. EtOAc in isohexane,0-100%, gradient elution) to afford the title compound, Intermediate C1as a yellow solid (3.07 g, 55%); R^(t) 2.59 min (Method 2); m/z 527/529(M+H)⁺ (ES⁺).

Example 11-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-(2-(phenylamino)pyrimidin-4-yloxy)naphthalen-1-yl)urea.

A heterogeneous mixture of a solution of Na₂CO₃ (3.84 g, 36 mmol) inwater (42 mL) and Intermediate A1 (10.5 g, 45.7 mmol) in isopropylacetate (130 mL, 1.082 mol) was stirred vigorously at RT for 5 min andwas then treated with phenyl carbonochloridate (5.77 ml, 45.7 mmol).Stirring of the mixture was continued for a further 4 hr after which thelayers were separated. The organic phase was added to a solution ofIntermediate B1 (10.0 g, 30.5 mmol) and triethylamine (423 μL, 3.05mmol) in ispropyl acetate (60 mL, 511 mmol). The reaction mixture waswarmed to 48° C. for 1 hr, then diluted with isopropyl acetate (190 mL)and cooled to RT for a further 18 hr, during which time a precipitateformed. The precipitate was isolated by filtration, washed withisopropyl acetate and then dried in vacuo at 40° C. to afford the titlecompound, Example 1 as a white solid (16.5 g, 92%); R^(t) 2.74 min(Method 2); m/z 584 (M+H)⁺ (ES⁺); ¹H NMR (400 MHz, DMSO-d₆) δ: 1.30 (9H,s), 2.41 (3H, s), 6.43 (1H, s), 6.58 (1H, d), 6.78 (1H, t), 6.97 (2H,t), 7.28 (2H, br m), 7.39 (2H, d), 7.40 (1H, d), 7.49 (2H, d), 7.56 (1H,m), 7.63 (1H, m), 7.82 (1H, dd), 7.95 (1H, d), 8.10 (1H, d), 8.40 (1H,d), 8.77 (1H, s), 9.16 (1H, br s), 9.50 (1H, br s).

Example 21-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((3-hydroxyphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea.

To a solution of Intermediate C1 (150 mg, 0.285 mmol) in DMF (2.0 mL)were added 3-aminophenol (52 mg, 0.477 mmol) and pTSA (96 mg, 0.51 mmol)and the resulting dark solution was heated to 60° C. for 16 hr. Thereaction mixture was cooled to RT and was then partitioned between EtOAc(20 mL) and saturated aq. NaHCO₃ (20 mL). The organic phase wasseparated and washed sequentially with saturated aq. NaHCO₃ (20 mL),water (20×20 mL) and brine (2×20 mL) and was then dried and evaporatedin vacuo. The residue was purified by flash column chromatography (SiO₂,40 g, EtOAc in isohexane, 0-100%, gradient elution) and the partiallypurified product so obtained was triturated with IPA to afford the titlecompound, Example 2, as an off white solid (56 mg, 32%); R^(t) 2.52 min(Method 2); m/z 600 (M+H)⁺ (ES⁺); ¹H NMR (400 MHz, DMSO-d₆) ä: 1.29 (9H,s), 2.40 (3H, s), 6.24 (1H, dd), 6.41 (1H, s), 6.47 (1H, d), 6.74 (1H,br t), 6.82 (1H, br d), 6.99 (1H, br s), 7.38-7.39 (3H, overlapping m),7.46 (2H, d), 7.56 (1H, dt), 7.62 (1H, dt), 7.81 (1H, dd), 7.92 (1H, d),8.07 (1H, d), 8.35 (1H, d), 8.74 (1H, s), 9.12 (2H, s), 9.36 (1H, s).

Example 31-(3-(tert-butyl)-1-(4-hydroxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2-(phenylamino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea.

To a solution of CDI (148 mg, 0.914 mmol) in DCM (2.0 mL) at RT wasadded Intermediate A3 (316 mg, 0.914 mmol). After 2 hr an aliquot of theresulting solution (1.0 mL, 0.50 mmol), was added to a solution ofIntermediate B1 (100 mg, 0.305 mmol) in THF (3.0 mL) and the reactionmixture maintained at RT for 18 hr and then partitioned between DCM (25mL) and saturated aq. NaHCO₃ (25 mL). The aq. layer was separated andwas extracted with DCM (25 mL) and the combined organic extracts weredried and evaporated in vacuo. The residue was purified by flash columnchromatography (SiO₂, 12 g, EtOAc in isohexane, 20%-100%, gradientelution) and the impure product so obtained was triturated with MeOH toafford1-(3-(tert-butyl)-1-(4-((tert-butyldimethylsilyl)oxy)phenyl)-1H-pyrazol-5-yl)-3-(4-((2-(phenylamino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea as an off white solid (70 mg,33%); R^(t) 3.74 min (Method 2); m/z 700 (M+H)⁺ (ES⁺).

To a solution of the TBDMS protected intermediate obtained above (70 mg,0.100 mmol) in THF (1.0 mL) was added TBAF (1 M solution in THF, 120 μL,0.12 mmol) and the reaction mixture kept at RT for 1 hr and thenpartitioned between DCM (50 mL) and saturated aq. NaHCO₃ (50 mL). Theaq. layer was separated and was extracted with DCM (50 mL) and thecombined organic extracts were dried and evaporated in vacuo. Theresidue was purified by SCX capture and release to afford the titlecompound, Example 3, as an off white solid (25 mg, 41%); R^(t) 2.38 min(Method 2); m/z 586 (M+H)⁺ (ES⁺); ¹H NMR (400 MHz, DMSO-d₆) ä: 1.28 (9H,s), 6.38 (1H, s), 6.57 (1H, d), 6.77 (1H, t), 6.94-6.96 (4H, overlappingm), 7.26-7.28 (2H, overlapping m), 7.35 (2H, d), 7.39 (1H, d), 7.55 (1H,dt), 7.62 (1H, dt), 7.80 (1H, d), 7.94 (1H, d), 8.08 (1H, d), 8.38 (1H,d), 8.67 (1H, s), 9.16 (1H, s), 9.51 (1H, s), 9.81 (1H, s).

Additional Compound Examples of the Invention

Ex. No. Structure Name and Analytical Data [Route] 4

1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((2-fluorophenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea. R^(t) 2.85 min (Method 2); m/z 602 (M +H)⁺ (ES⁺); ¹H NMR ä: 1.28 (9H, s), 2.40 (3H, s), 6.42 (1H, s), 6.51 (1H,d), 6.83 (1H, t), 6.99 (1H, m), 7.09 (1H, m), 7.29 (1H, dt), 7.37-7.39(3H, overlapping m), 7.47 (2H, d), 7.57 (1H, dt), 7.63 (1H, dt), 7.81(1H, dd), 7.90 (1H, d), 8.06 (1H, d), 8.31 (1H, d), 8.76 (1H, s), 9.01(1H, s), 9.13 (1H, s), [B] 5

1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((2-methoxyphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea. R^(t) 2.84 min (Method 2); m/z614 (M + H)⁺ (ES⁺); ¹H NMR ä: 1.29 (9H, s), 2.40 (3H, s), 3.76 (3H, s)6.42 (1H, s), 6.51 (1H, t), 6.56 (1H, d), 6.85 (1H, t), 6.91 (1H, dd),7.38-7.43 (4H, overlapping m), 7.47 (2H, d), 7.56 (1H, dt), 7.62 (1H,dt), 7.81 (1H, dd), 7.86 (1H, s), 7.95 (1H, d), 8.09 (1H, d), 8.36 (1H,d), 8.76 (1H, s), 9.14 (1H, s). [B] 6

1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((2-chlorophenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea. R^(t) 3.05 min (Method 2); m/z618 (M + H)⁺ (ES⁺); ¹H NMR ä: 1.29 (9H, s), 2.40 (3H, s), 6.42 (1H, s),6.51 (1H, d), 6.99-7.01 (2H, overlapping m), 7.36-7.38 (5H, overlappingm), 7.46 (2H, d), 7.57 (1H, dt), 7.63 (1H, dt), 7.81 (1H, dd), 7.91 (1H,d), 8.07 (1H, d), 8.31 (1H, d), 8.65 (1H, s), 8.76 (1H, s), 9.12 (1H,s). [B] 7

1-(3-(tert-butyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2-(phenylamino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea. R^(t) 2.69 min (Method 2); m/z600 (M + H)⁺ (ES⁺); ¹H NMR ä: 1.29 (9H, s), 3.84 (3H, s), 6.40 (1H, s),6.57 (1H, d), 6.77 (1H, t), 6.96 (1H, t), 7.13 (2H, d), 7.27 (2H, d),7.39 (1H, d), 7.49 (2H, d), 7.55 (1H, dt), 7.61 (1H, dt), 7.81 (1H, d),7.94 (1H, d), 8.08 (1H, d), 8.38 (1H, d), 8.70 (1H, s), 9.13 (1H, s),9.50 (1H, s). [B] 8

1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((2,4-dimethoxyphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea. R^(t) 2.78 min (Method 2); m/z644 (M + H)⁺ (ES⁺); ¹H NMR ä: 1.29 (9H, s), 2.99 (3H, s), 3.67 (3H, s),3.71 (3H, s), 6.19 (1H, d), 6.41 (1H, s), 6.46 (1H, d), 6.49 (1H, d),7.18 (1H, d), 7.36 (1H, d), 7.39 (2H, d), 7.47 (2H, d), 7.55 (1H, dt),7.61 (1H, dt), 7.80 (1H, d), 7.85 (1H, s), 7.92 (1H, d), 8.07 (1H, d),8.28 (1H, d), 8.78 (1H, s), 9.14 (1H, s). [B] 9

1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((4-hydroxyphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea. R^(t) 2.42 min (Method 2); m/z600 (M + H)⁺ (ES⁺); ¹H NMR ä: 1.29 (9H, s), 2.40 (3H, s), 6.40-6.45 (4H,overlapping m), 7.08 (2H, br s), 7.36-7.39 (3H, overlapping m), 7.47(2H, d), 7.55 (1H, dt), 7.62 (1H, dt), 7.80 (1H, d), 7.94 (1H, d), 8.08(1H, d), 8.30 (1H, d), 8.82 (1H, s), 8.93 (1H, s), 9.17 (1H, s), 9.20(1H, br s). [B] 10

1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((2,5-dimethylphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea. R^(t) 2.91 min (Method 2); m/z612 (M + H)⁺ (ES⁺); ¹H NMR ä: 1.28 (9H, s), 2.00 (3H, s), 2.06 (3H, s),2.39 (3H, s), 6.39-6.40 (2H, overlapping m), 6.72 (1H, d), 6.95- 6.98(2H, overlapping m), 7.35-7.38 (3H, overlapping m), 7.46 (2H, d) 7.57(1H, dt), 7.62 (1H, dt), 7.81 (1H, d), 7.90 (1H, d), 8.06 (1H, d), 8.25(1H, d), 8.58 (1H, s), 8.87 (1H, s), 9.18 (1H, s). [B] 11

1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-(p-tolylamino)pyrimidin-4-yl)oxy) naphthalen-1-yl)urea. R^(t)2.81 min (Method 2); m/z 598 (M + H)⁺ (ES⁺); ¹H NMR ä: 1.29 (9H, s),2.13 (3H, s), 2.40 (3H, s), 6.43 (1H, s), 6.54 (1H, d), 6.80 (2H, d),7.16 (2H, br s), 7.37-7.39 (3H, overlapping m) 7.47 (2H, d), 7.55 (1H,dt), 7.62 (1H, dt), 7.80 (1H, d), 7.92 (1H, d), 8.09 (1H, d), 8.37 (1H,d), 8.79 (1H, s), 9.16 (1H, s), 9.40 (1H, s). [B] 12

1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-(m-tolylamino)pyrimidin-4-yl)oxy) naphthalen-1-yl)urea. R^(t)2.88 min (Method 2); m/z 598 (M + H)⁺ (ES⁺); ¹H NMR ä: 1.29 (9H, s),1.95 (3H, s), 2.40 (3H, s), 6.41 (1H, s), 6.57-6.60 (2H, overlapping m),6.85 (1H, t), 7.04 (1H, br d), 7.11 (1H, br s) 7.37-7.40 (3H,overlapping m), 7.47 (2H, d), 7.55 (1H, dt), 7.62 (1H, dt), 7.80 (1H,d), 7.97 (1H, d), 8.09 (1H, d), 8.39 (1H, d), 8.82 (1H, s), 9.18 (1H,s), 9.46 (1H, s). [B] 13

1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((3-chlorophenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea. R^(t) 2.95 min (Method 2); m/z 618 (M +H)⁺ (ES⁺); ¹H NMR ä: 1.29 (9H, s), 2.40 (3H, s), 6.41 (1H, s), 6.65 (1H,a), 6.81 (1H, d), 7.00 (1H, t), 7.23 (1H, br d) 7.36-7.41 (3H,overlapping m), 7.46-7.49 (3H, overlapping m), 7.55 (1H, dt), 7.62 (1H,dt), 7.80 (1H, d), 7.96 (1H, d), 8.08 (1H, d), 8.46 (1H, d), 8.80 (1H,s), 9.14 (1H, s), 9.71 (1H, s). [B] 14

1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((3-methoxyphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea. R^(t) 2.74 min (Method 2); m/z614 (M + H)⁺ (ES⁺); ¹H NMR ä: 1.29 (9H, s), 2.40 (3H, s), 3.52 (3H, s),6.38 (1H, d), 6.42 (1H, s), 6.56 (1H, d), 6.88-6.95 (2H, overlapping m),7.08 (1H, br s) 7.37-7.40 (3H, overlapping m), 7.47 (2H, d), 7.55 (1H,dt), 7.62 (1H, dt), 7.81 (1H, d), 7.95 (1H, d), 8.08 (1H, d), 8.39 (1H,d), 8.78 (1H, s), 9.14 (1H, s), 9.48 (1H, s). [B] 15

1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((3-fluorophenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea. R^(t) 2.80 min (Method 2); m/z 602 (M +H)⁺ (ES⁺); ¹H NMR ä: 1.29 (9H, s), 2.40 (3H, s), 6.42 (1H, s), 6.57 (1H,dt), 6.65 (1H, d), 7.02 (1H, q), 7.24 (1H, br d) 7.37-7.41 (3H,overlapping m), 7.48 (2H, d), 7.55 (1H, dt), 7.62 (1H, dt), 7.80 (1H,dd), 7.96 (1H, d), 8.10 (1H, d), 8.45 (1H, d), 8.84 (1H, s), 9.19 (1H,s), 9.74 (1H, s). [B] 16

1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((4-chlorophenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea. R^(t) 2.90 min (Method 2); m/z 618 (M +H)⁺ (ES⁺); ¹H NMR ä: 1.28 (9H, s), 2.40 (3H, s), 6.46 (1H, s), 6.65 (1H,d), 6.65 (1H, d), 7.04 (2H, d), 7.27 (1H, br d) 7.37-7.42 (3H,overlapping m), 7.48 (2H, d), 7.55 (1H, dt), 7.62 (1H, dt), 7.80 (1H,dd), 7.90 (1H, d), 8.08 (1H, d), 8.41 (1H, d), 8.79 (1H, s), 9.17 (1H,s), 9.70 (1H, s). [B] 17

1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((4-methoxyphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea. R^(t) 2.66 min (Method 2); m/z614 (M + H)⁺ (ES⁺); ¹H NMR ä: 1.29 (9H, s), 2.40 (3H, s), 3.62 (3H, s),6.40 (1H, s), 6.52 (1H, d), 6.58 (2H, d), 7.15 (2H, br s), 7.37-7.39(3H, overlapping m), 7.47 (2H, d), 7.54 (1H, dt), 7.61 (1H, dt), 7.80(1H, dd), 7.91 (1H, d), 8.08 (1H, d), 8.34 (1H, d), 8.83 (1H, s), 9.20(1H, s), 9.32 (1H, s). [B] 18

1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((4-chloro-2-methylphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea. R^(t) 2.95 min (Method 2); m/z632 (M + H)⁺ (ES⁺); ¹H NMR ä: 1.28 (9H, s), 2.11 (3H, s), 2.40 (3H, s),6.42 (1H, s), 6.44 (1H, d), 6.91 (1H, dd), 7.15-7.17 (2H, overlappingm), 7.35-7.38 (3H, overlapping m), 7.47 (2H, d), 7.57 (1H, dt), 7.63(1H, dt), 7.80 (1H, dd), 7.88 (1H, d), 8.06 (1H, d), 8.27 (1H, d), 8.73(2H, d), 9.09 (1H, s). [B] 19

1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((2-chlorophenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea. R^(t) 3.04 min (Method 2); m/z 662, 664(M + H)⁺ (ES⁺); ¹H NMR ä: 1.29 (9H, s), 2.39 (3H, s), 6.41 (1H, s), 6.49(1H, d), 6.95 (1H, dt), 7.05 (1H, dt), 7.35-7.39 (4H, overlapping m),7.46 (2H, d), 7.54-7.59 (2H, overlapping m), 7.63 (1H, dt), 7.81 (1H,dd), 7.90 (1H, d), 8.07 (1H, d), 8.31 (1H, d), 8.54 (1H, s), 8.79 (1H,s), 9.15 (1H, s). [B] 20

1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((2-isopropylphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea. R^(t) 2.92 min (Method 2); m/z626 (M + H)⁺ (ES⁺); ¹H NMR ä: 1.07 (6H, d), 1.29 (9H, s), 2.39 (3H, s),3.09 (1H, m) 6.26 (1H, d), 6.38 (1H, s), 7.00 (1H, dt), 7.09-7.12 (2H,overlapping m), 7.24 (1H, dd), 7.34-7.36 (3H, overlapping m), 7.47 (2H,d), 7.57- 7.64 (2H, overlapping m), 7.81 (1H, d), 7.85 (1H, d), 8.08(1H, d), 8.16 (1H, d), 8.72 (1H, s), 9.03 (1H, s), 9.33 (1H, s). [B] 21

1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-(o-tolylamino)pyrimidin-4-yl)oxy) naphthalen-1-yl)urea. R^(t)2.78 min (Method 2); m/z 598 (M + H)⁺ (ES⁺); ¹H NMR ä: 1.29 (9H, s),2.12 (3H, s), 2.39 (3H, s) 6.36 (1H, d), 6.40 (1H, s), 6.89-6.94 (2H,overlapping m), 7.09 (1H, d), 7.15 (1H, d), 7.35-7.37 (3H, overlappingm), 7.47 (2H, d), 7.57-7.64 (2H, overlapping m), 7.82 (1H, d), 7.87 (1H,d), 8.07 (1H, d), 8.24 (1H, d), 8.66 (1H, s), 8.88 (1H, s), 9.21 (1H,s). [B] 22

1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((4-ethoxyphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea. R^(t) 2.80 min (Method 2); m/z 628 (M+H)⁺ (ES⁺); ¹H NMR ä: 1.20 (3H, t), 1.29 (9H, s), 2.40 (3H, s), 3.85 (2H,q), 6.42 (1H, s), 6.52-6.56 (3H, overlapping m), 7.12 (2H, br s),7.37-7.39 (3H, overlapping m), 7.47 (2H, d), 7.55 (1H, t), 7.61 (1H, t),7.80 (1H, d), 7.93 (1H, d), 8.08 (1H, d), 8.33 (1H, d), 8.78 (1H, s),9.16 (1H, s), 9.32 (1H, s). [B] 23

1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((4-fluorophenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea. R^(t) 2.83 min (Method 2); m/z 602 (M +H)⁺ (ES⁺); ¹H NMR ä: 1.29 (9H, s), 2.39 (3H, s), 6.42 (1H, s), 6.59 (1H,d), 6.82 (2H, br t), 7.26 (2H, br s), 7.37-7.39 (3H, overlapping m),7.47 (2H, d), 7.55 (1H, dt), 7.60 (1H, dt), 7.79 (1H, dd), 7.89 (1H, d),8.08 (1H, d), 8.38 (1H, d), 8.84 (1H, s), 9.22 (1H, s), 9.56 (1H, s).[B] 24

1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((4-hydroxy-2-methylphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1- yl)urea. R^(t) 2.32 min (Method2); m/z 614 (M + H)⁺ (ES⁺); ¹H NMR ä: 1.28 (9H, s), 2.00 (3H, s), 2.39(3H, s), 6.23 (1H, d), 6.38-6.39 (2H, overlapping m), 6.52 (1H, d), 6.78(1H, d), 7.36-7.38 (3H, overlapping m), 7.46 (2H, d), 7.57 (1H, dt),7.62 (1H, dt), 7.81 (1H, dd), 7.86 (1H, d), 8.05 (1H, d), 8.15 (1H, d),8.47 (1H, s), 8.87 (1H, s), 9.12 (1H, s), 9.19 (1H, s). [B] 25

1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((4-hydroxy-3-methoxyphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1- yl)urea. R^(t) 2.43 min (Method2); m/z 630 (M + H)⁺ (ES⁺); ¹H NMR ä: 1.29 (9H, s), 2.40 (3H, s), 3.43(3H, br s), 6.42 (2H, br s), 6.46 (1H, d), 6.75 (1H, br s), 7.04 (1H, brs), 7.37-7.39 (3H, overlapping m), 7.47 (2H, d), 7.56 (1H, dt), 7.62(1H, dt), 7.81 (1H, dd), 7.92 (1H, d), 8.07 (1H, d), 8.32 (1H, d), 8.44(1H, s), 8.83 (1H, s), 9.18 (1H, s), 9.20 (1H, br s). [B] 26

1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((3-hydroxy-4-methylphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1- yl)urea. R^(t) 2.59 min (Method2); m/z 614 (M + H)⁺ (ES⁺); ¹H NMR ä: 1.29 (9H, s), 1.97 (3H, s), 2.39(3H, s), 6.41 (1H, s), 6.42 (1H, d), 6.70 (2H, br dd), 7.01 (1H, br s),7.37-7.39 (3H, overlapping m), 7.47 (2H, d), 7.55 (1H, dt), 7.61 (1H,dt), 7.81 (1H, dd), 7.90 (1H, d), 8.07 (1H, d), 8.33 (1H, d), 8.88 (1H,s), 9.06 (1H, s), 9.22 (1H, s), 9.30 (1H, s), [B] 27

1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((3,4-dimethoxyphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea. R^(t) 2.58 min (Method 2); m/z644 (M + H)⁺ (ES⁺); ¹H NMR ä: 1.29 (9H, s), 2.40 (3H, s), 3.44 (3H, s),3.61 (3H, s), 6.40 (1H, s), 6.53 (1H, d), 6.61 (1H, br d), 6.85 (1H, brs), 7.03 (1H, br s), 7.37-7.39 (3H, overlapping m), 7.47 (2H, d), 7.55(1H, dt), 7.61 (1H, dt), 7.81 (1H, dd), 7.91 (1H, d), 8.07 (1H, d), 8.35(1H, d), 8.80 (1H, s), 9.16 (1H, s), 9.29 (1H, s). [B] 28

1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((3-chloro-4-methoxyphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1- yl)urea. R^(t) 2.82 min (Method2); m/z 648 (M + H)⁺ (ES⁺); ¹H NMR ä: 1.29 (9H, s), 2.40 (3H, s), 3.70(3H, s), 6.39 (1H, s), 6.60 (1H, d), 6.83 (1H, br d), 7.17 (1H, br s),7.38-7.40 (4H, overlapping m), 7.47 (2H, d), 7.54 (1H, dt), 7.61 (1H,dt), 7.79 (1H, dd), 7.93 (1H, d), 8.07 (1H, d), 8.38 (1H, d), 8.86 (1H,s), 9.19 (1H, s), 9.51 (1H, s). [B] 29

1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((3-fluoro-4-hydroxyphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea. R^(t) 2.43 min (Method 2); m/z618 (M + H)⁺ (ES⁺); ¹H NMR ä: 1.29 (9H, s), 2.40 (3H, s), 6.42 (1H, s),6.53 (1H, d), 6.61 (1H, br t), 6.89 (1H, br s), 7.18 (1H, br s), 7.37-7.39 (3H, overlapping m), 7.47 (2H, d), 7.55 (1H, dt), 7.61 (1H, dt),7.78 (1H, dd), 7.95 (1H, d), 8.08 (1H, d), 8.35 (1H, d), 8.87 (1H, s),9.19 (1H, s), 9.29 (1H, br s), 9.40 (1H, s). [B] 30

1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((2-fluoro-4-hydroxyphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea. R^(t) 2.49 min (Method 2); m/z618 (M + H)⁺ (ES⁺); ¹H NMR ä: 1.28 (9H, s), 2.39 (3H, s), 6.34 (1H, d),6.38 (1H, br d), 6.41 (1H, s), 6.51 (1H, dd), 7.02 (1H, t), 7.36-7.38(3H, overlapping m), 7.46 (2H, d), 7.57 (1H, dt), 7.62 (1H, dt), 7.80(1H, dd), 7.89 (1H, d), 8.05 (1H, d), 8.20 (1H, d), 8.68 (1H, s), 8.77(1H, s), 9.11 (1H, s), 9.63 (1H, s). [B] 31

1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((2-chloro-4-hydroxyphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1- yl)urea. R^(t) 2.67 min (Method2); m/z 634 (M + H)⁺ (ES⁺); ¹H NMR ä: 1.28 (9H, s), 2.39 (3H, s), 6.33(1H, d), 6.41 (1H, s), 6.54 (1H, dd), 6.78 (1H, dd), 7.09 (1H, d),7.36-7.38 (3H, overlapping m), 7.46 (2H, d), 7.57 (1H, dt), 7.63 (1H,dt), 7.80 (1H, dd), 7.89 (1H, d), 8.05 (1H, d), 8.20 (1H, d), 8.57 (1H,s), 8.78 (1H, s), 9.12 (1H, s), 9.69 (1H, s). [B] 32

1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((2,4-dihydroxyphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea. R^(t) 2.24 min (Method 2); m/z616 (M + H)⁺ (ES⁺); ¹H NMR ä: 1.29 (9H, s), 2.40 (3H, s), 5.92 (1H, brs), 6.25 (1H, d), 6.38 (1H, d), 6.42 (1H, s), 7.00 (1H, br s), 7.36-7.38(3H, overlapping m), 7.47 (2H, d), 7.56 (1H, dt), 7.62 (1H, dt), 7.80(1H, dd), 7.89 (1H, br s), 7.93 (1H, d), 8.07 (1H, d), 8.24 (1H, d),8.84 (1H, s), 8.97 (1H, s), 9.18 (1H, s), 9.61 (1H, s). [B] 33

1-(3-(tert-butyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((4-hydroxyphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1- yl)urea. R^(t) 2.31 min (Method2); m/z 616 (M + H)⁺ (ES⁺); ¹H NMR ä: 1.29 (9H, s), 3.84 (3H, s),6.42-6.45 (4H, overlapping m), 7.08- 7.11 (4H, overlapping m), 7.37 (1H,d), 7.50 (2H, d), 7.56 (1H, dt), 7.62 (1H, dt), 7.81 (1H, dd), 7.95 (1H,d), 8.08 (1H, d), 8.30 (1H, d), 8.77 (1H, s), 8.93 (1H, br s), 9.16 (1H,s), 9.19 (1H, br s). [A]Biological Testing: Experimental MethodsEnzyme Inhibition Assays

The kinase enzyme binding activities of compounds disclosed herein weredetermined using a proprietary assay which measures active site-directedcompetition binding to an immobilized ligand (Fabian, M. A. et al.,Nature Biotechnol., 2005, 23:329-336). These assays were conducted byDiscoverX (formerly Ambit; San Diego, Calif.). The Kd value(Dissociation constant value) was calculated as the index of affinity ofthe compounds to each kinase.

Enzyme Inhibition Assays

The enzyme inhibitory activities of compounds disclosed herein weredetermined by FRET using synthetic peptides labelled with both donor andacceptor fluorophores (Z-LYTE, Invitrogen Ltd., Paisley, UK).

p38 MAPKα Enzyme Inhibition

The inhibitory activities of test compounds against the p38 MAPKαisoform (MAPK14: Invitrogen), were evaluated indirectly by determiningthe level of activation phosphorylation of the down-stream molecule,MAPKAP-K2. The p38 MAPKα protein (80 ng/mL, 2.5 μL) was mixed with thetest compound (2.5 μL of either 4 μg/mL, 0.4 μg/mL, 0.04 μg/mL or 0.004μg/mL) for 2 hr at RT. The mix solution (2.5 μL) of the p38α inactivetarget MAPKAP-K2 (Invitrogen, 600 ng/mL) and FRET peptide (8 μM; aphosphorylation target for MAPKAP-K2) was then added and the kinasereaction was initiated by adding ATP (40 μM, 2.5 μL). The mixture wasincubated for 1 hr at RT. Development reagent (protease, 5 μL) was addedfor 1 hr prior to detection in a fluorescence microplate reader(Varioskan® Flash, ThermoFisher Scientific).

p38 MAPKγ Enzyme Inhibition

The inhibitory activities of compounds of the invention against p38MAPKγ(MAPK12: Invitrogen), were evaluated in a similar fashion to thatdescribed hereinabove. The enzyme (800 ng/mL, 2.5 μL) was incubated withthe test compound (2.5 μL at either 4 μg/mL, 0.4 μg/mL, 0.04 μg/mL, or0.004 μg/mL) for 2 hr at RT. The FRET peptides (8 μM, 2.5 μL), andappropriate ATP solution (2.5 μL, 400 μM) was then added to theenzymes/compound mixtures and incubated for 1 hr. Development reagent(protease, 5 μL) was added for 1 hr prior to detection in a fluorescencemicroplate reader (Varioskan® Flash, Thermo Scientific).

c-Src and Syk Enzyme Inhibition

The inhibitory activities of compounds of the invention against c-Srcand Syk enzymes (Invitrogen), were evaluated in a similar fashion tothat described hereinabove. The relevant enzyme (3000 ng/mL or 2000ng/mL respectively, 2.5 μL) was incubated with the test compound (either4 μg/mL, 0.4 μg/mL, 0.04 μg/mL, or 0.004 μg/mL, 2.5 μL each) for 2 hr atRT. The FRET peptides (8 μM, 2.5 μL), and appropriate ATP solutions (2.5μL, 800 μM for c-Src, and 60 μM ATP for Syk) were then added to theenzyme/compound mixtures and incubated for 1 hr. Development reagent(protease, 5 μL) was added for 1 hr prior to detection in a fluorescencemicroplate reader (Varioskan® Flash, ThermoFisher Scientific).

GSK 3α Enzyme Inhibition

The inhibitory activities of test compounds against the GSK 3α enzymeisoform (Invitrogen), were evaluated by determining the level ofactivation/phosphorylation of the target peptide. The GSK3-α protein(500 ng/mL, 2.5 μL) was mixed with the test compound (2.5 μL at either 4μg/mL, 0.4 μg/mL, 0.04 μg/mL, or 0.004 μg/mL) for 2 hr at RT. The FRETpeptide (8 μM, 2.5 μL), which is a phosphorylation target for GSK3α, andATP (40 μM, 2.5 μL) were then added to the enzyme/compound mixture andthe resulting mixture incubated for 1 hr. Development reagent (protease,5 μL) was added for 1 hr prior to detection in a fluorescence microplatereader (Varioskan® Flash, ThermoFisher Scientific).

In all cases, the site-specific protease cleaves non-phosphorylatedpeptide only and eliminates the FRET signal. Phosphorylation levels ofeach reaction were calculated using the ratio of coumarin emission(donor) over fluorescein emission (acceptor), for which low ratiosindicate high phosphorylation and high ratios indicate lowphosphorylation levels. The percentage inhibition of each reaction wascalculated relative to non-inhibited control and the 50% inhibitoryconcentration (IC₅₀ value) was then calculated from theconcentration-response curve.

Cellular Assays

LPS-induced TNFα/IL-8 Release in d-U937 Cells

U937 cells, a human monocytic cell line, were differentiated intomacrophage-type cells by incubation with PMA (100 ng/mL) for 48 to 72hr. Cells were pre-incubated with final concentrations of test compoundfor 2 hr and were then stimulated with LPS (0.1 μg/mL; from E. Coli:O111:B4, Sigma) for 4 hr. The supernatant was collected fordetermination of TNFα and IL-8 concentrations by sandwich ELISA(Duo-set, R&D systems). The inhibition of TNFα production was calculatedas a percentage of that achieved by 10 μg/mL of BIRB796 at eachconcentration of test compound by comparison against vehicle control.The relative 50% effective concentration (REC₅₀) was determined from theresultant concentration-response curve. The inhibition of IL-8production was calculated at each concentration of test compound bycomparison with vehicle control. The 50% inhibitory concentration (IC₅₀)was determined from the resultant concentration-response curve.

LPS-induced TNFα Release in THP-1 Cells

THP-1 cells, a human monocytic cell line, were stimulated with 3 μg/mLof LPS (from E. Coli; 0111:B4, Sigma) for 4 hr and the supernatantcollected for determination of the TNFα concentration by sandwich ELISA(Duo-set, R&D systems). The inhibition of TNFα production was calculatedat each concentration by comparison with vehicle control. The 50%inhibitory concentration (IC₅₀) was determined from the resultantconcentration-response curve.

Poly I:C-induced ICAM-1 Expression in BEAS2B Cells

Poly I:C was used in these studies as a simple, RNA virus mimic. PolyI:C-Oligofectamine mixture (1 μg/mL Poly I:C, ±2% Oligofectamine, 25 μL;Invivogen Ltd., San Diego, Calif., and Invitrogen, Carlsbad, Calif.,respectively) was transfected into BEAS2B cells (human bronchialepithelial cells, ATCC). Cells were pre-incubated with finalconcentrations of test compounds for 2 hr and the level of ICAM-1expression on the cell surface was determined by cell-based ELISA. At atime point 18 hr after poly I:C transfection, cells were fixed with 4%formaldehyde in PBS (100 μL) and then endogenous peroxidase was quenchedby the addition of washing buffer (100 μL, 0.05% Tween in PBS:PBS-Tween) containing 0.1% sodium azide and 1% hydrogen peroxide. Cellswere washed with wash-buffer (3×200 μL). and after blocking the wellswith 5% milk in PBS-Tween (100 μL) for 1 hr, the cells were incubatedwith anti-human ICAM-1 antibody (50 μL; Cell Signaling Technology,Danvers, Mass.) in 1% BSA PBS overnight at 4° C.

The cells were washed with PBS-Tween (3×200 μL) and incubated with thesecondary antibody (100 μL; HRP-conjugated anti-rabbit IgG, Dako Ltd.,Glostrup, Denmark). The cells were then incubated with of substrate (50μL) for 2-20 min, followed by the addition of stop solution (50 μL, 1NH₂SO₄). The ICAM-1 signal was detected by reading and reading theabsorbance at 450 nm against a reference wavelength of 655 nm using aspectrophotometer. The cells were then washed with PBS-Tween (3×200 μL)and total cell numbers in each well were determined by readingabsorbance at 595 nm after Crystal Violet staining (50 μL of a 2%solution in PBS) and elution by 1% SDS solution (100 μL) in distilledwater. The measured OD 450-655 readings were corrected for cell numberby dividing with the OD595 reading in each well. The inhibition ofICAM-1 expression was calculated at each concentration of test compoundby comparison with vehicle control. The 50% inhibitory concentration(IC₅₀) was determined from the resultant concentration-response curve.

Cell Mitosis Assay

Peripheral blood mononucleocytes (PBMCs) from healthy subjects wereseparated from whole blood (Quintiles, London, UK) using a densitygradient (Histopaque®-1077, Sigma-Aldrich, Poole, UK). The PBMCs (3million cells per sample) were subsequently treated with 2% PHA(Sigma-Aldrich, Poole, UK) for 48 hr, followed by a 20 hr exposure tovarying concentrations of test compounds. At 2 hr before collection,PBMCs were treated with demecolcine (0.1 μg/mL; Invitrogen, Paisley,UK,) to arrest cells in metaphase. To observe mitotic cells, PBMCs werepermeabilised and fixed by adding Intraprep (50 μL; Beckman Coulter,France), and stained with anti-phospho-histone 3 (0.26 ng/L; #9701; CellSignalling, Danvers, Mass.) and propidium iodide (1 mg/mL;Sigma-Aldrich, Poole, UK,) as previously described (Muehlbauer P. A. andSchuler M. J., Mutation Research, 2003, 537:117-130). Fluorescence wasobserved using an ATTUNE flow cytometer (Invitrogen, Paisley, UK),gating for lymphocytes. The percentage inhibition of mitosis wascalculated for each treatment relative to vehicle (0.5% DMSO) treatment.

Rhinovirus-induced IL-8 Release and ICAM-1 Expression

Human rhinovirus RV16 was obtained from the American Type CultureCollection (Manassas, Va.). Viral stocks were generated by infectingHela cells with HRV until 80% of the cells were cytopathic.

BEAS2B cells were infected with HRV at an MOI of 5 and incubated for 2hr at 33° C. with gentle shaking for to promote absorption. The cellswere then washed with PBS, fresh media added and the cells wereincubated for a further 72 hr. The supernatant was collected for assayof IL-8 concentrations using a Duoset ELISA development kit (R&Dsystems, Minneapolis, Minn.).

The level of cell surface ICAM-1 expression was determined by cell-basedELISA. At 72 hr after infection, cells were fixed with 4% formaldehydein PBS. After quenching endogenous peroxidase by adding 0.1% sodiumazide and 1% hydrogen peroxide, wells were washed with wash-buffer(0.05% Tween in PBS: PBS-Tween). After blocking well with 5% milk inPBS-Tween for 1 hr, the cells were incubated with anti-human ICAM-1antibody in 5% BSA PBS-Tween (1:500) overnight. Wells were washed withPBS-Tween and incubated with the secondary antibody (HRP-conjugatedanti-rabbit IgG, Dako Ltd.). The ICAM-1 signal was detected by addingsubstrate and reading at 450 nm with a reference wavelength of 655 nmusing a spectrophotometer. The wells were then washed with PBS-Tween andtotal cell numbers in each well were determined by reading absorbance at595 nm after Crystal Violet staining and elution by 1% SDS solution. Themeasured OD₄₅₀₋₆₅₅ readings were corrected for cell number by dividingwith the OD₅₉₅ reading in each well. Compounds were added 2 hr beforeHRV infection and 2 hr after infection when non-infected HRV was washedout.

Assessment of HRV16 Induced CPE in MRC5 Cells

MRC-5 cells were infected with HRV16 at an MOI of 1 in DMEM containing5% FCS and 1.5 mM MgCl₂, followed by incubation for 1 hr at 33° C. topromote adsorption. The supernatants were aspirated, and then freshmedia added followed by incubation for 4 days. Where appropriate, cellswere pre-incubated with compound or DMSO for 2 hr, and the compounds andDMSO added again after washout of the virus.

Supernatants were aspirated and incubated with methylene blue solution(100 μL, 2% formaldehyde, 10% methanol and 0.175% Methylene Blue) for 2hr at RT. After washing, 1% SDS in distilled water (100 μL) was added toeach well, and the plates were shaken lightly for 1-2 hr prior toreading the absorbance at 660 nm. The percentage inhibition for eachwell was calculated. The IC₅₀ value was calculated from theconcentration-response curve generated by the serial dilutions of thetest compounds.

In Vitro RSV Virus Load in Primary Bronchial Epithelial Cells

Normal human bronchial epithelial cells (NHBEC) grown in 96 well plateswere infected with RSV A2 (Strain A2, HFA, Salisbury, UK) at an MOI of0.001 in the LHC8 Media:RPMI-1640 (50:50) containing 15 mM magnesiumchloride and incubated for 1 hr at 37° C. for adsorption. The cells werethen washed with PBS (3×200 μL), fresh media (200 μL) was added andincubation continued for 4 days. Where appropriate, cells werepre-incubated with the compound or DMSO for 2 hr, and then added againafter washout of the virus.

The cells were fixed with 4% formaldehyde in PBS solution (50 μL) for 20min, washed with washing buffer (3×200 μL; PBS including 0.5% BSA and0.05% Tween-20) and incubated with blocking solution (5% condensed milkin PBS) for 1 hr. Cells were then washed with washing buffer (3×200 μL)and incubated for 1 hr at RT with anti-RSV (2F7) F-fusion proteinantibody (40 μL; mouse monoclonal, lot 798760, Cat. No. ab43812, Abcam)in 5% BSA in PBS-tween). After washing, cells were incubated with anHRP-conjugated secondary antibody solution (50 μL) in 5% BSA inPBS-Tween (lot 00053170, Cat.No. P0447, Dako) and then TMB substrate (50μL; substrate reagent pack, lot 269472, Cat. No. DY999, R&D Systems,Inc.) was added. This reaction was stopped by the addition of 2N H₂SO₄(50 μL) and the resultant signal was determined colorimetrically (OD:450 nm with a reference wavelength of 655 nm) in a microplate reader(Varioskan® Flash, ThermoFisher Scientific).

Cells were then washed and a 2.5% crystal violet solution (50 μL; lot8656, Cat. No, PL7000, Pro-Lab Diagnostics) was applied for 30 min.After washing with washing buffer, 1% SDS in distilled water (100 μL)was added to each well, and plates were shaken lightly on the shaker for1 hr prior to reading the absorbance at 595 nm. The measured OD₄₅₀₋₆₅₅readings were corrected to the cell number by dividing the OD₄₅₀₋₆₅₅ bythe OD₅₉₅ readings. The percentage inhibition for each well wascalculated and the IC₅₀ value was calculated from theconcentration-response curve generated from the serial dilutions ofcompound.

The Effect of Test Compounds on Cell Viability: MTT Assay

Differentiated U937 cells were pre-incubated with each test compound(final concentration 1 μg/mL or 10 μg/mL in 200 μL media indicatedbelow) under two protocols: the first for 4 hr in 5% FCS RPMI1640 mediaand the second in 10% FCS RPMI1640 media for 24 h. The supernatant wasreplaced with new media (200 μL) and MTT stock solution (10 μL, 5 mg/mL)was added to each well. After incubation for 1 hr the media wereremoved, DMSO (200 μL) was added to each well and the plates were shakenlightly for 1 hr prior to reading the absorbance at 550 nm. Thepercentage loss of cell viability was calculated for each well relativeto vehicle (0.5% DMSO) treatment. Consequently an apparent increase incell viability for drug treatment relative to vehicle is tabulated as anegative percentage.

Cytokine Production in Sputum Macrophages from COPD.

Patients with COPD were inhaled with a nebulised solution of 3% (w/v)hypertonic saline using an ultrasonic nebuliser (Devilbiss, Carthage,Mo.) with tidal breathing for 5 min. This procedure was repeated amaximum of three times until enough sputum was obtained. The sputumsamples were homogenized and mixed vigorously using a vortex mixer in0.02% v/v dithiothreitol (DTT) solution. The samples were re-suspendedin PBS (40 mL) followed by centrifugation at 1500 rpm at 4° C. for 10min to obtain sputum cell pellets. The pellets were washed twice withPBS (40 mL). The sputum cells were then re-suspended in macrophageserum-free medium (macrophage-SFM, Life technologies, Paisley, UK; toachieve 2×10⁶/well in a 24 well plate) containing 20 U/mL penicillin,0.02 mg/mL streptomycin and 5 μg/mL amphotericin B and seeded on highbound 96-well plate, followed by incubation for 2 hr at 37° C. and at 5%CO₂ to allow the macrophages to attach to the bottom of the plate. Thecells on the plate were washed with fresh macrophage-SFM (200 μL/well)to remove neutrophils and other contaminated cells. The adherent cells(mainly sputum macrophages) on the plate were used for further analysis.Sputum induction and isolation were conducted in Quintiles Drug ResearchUnit at Guys Hospital and ethics approval and written informed consentwas obtained by Quintiles.

Where appropriate, 1 μL of a solution containing either the testcompound or reference article at the stated concentrations oralternatively 1 μL of DMSO as the vehicle control was added to each well(200 μL in media) and the cells were incubated for 2 hr. The cells werestimulated with LPS solution (50 μL, final concentration: 1 μg/mL) andincubated for 4 hr at 37° C. and 5% CO₂. The supernatant was thencollected and kept at −80° C. Millipore's luminex kits were used tomeasure the four analytes. After thawing the supernatant, the magneticantibody beads were multiplexed and incubated in a 96-well plate withstandard, background solution or the appropriate volume of sampleovernight with shaking at 4° C. After washing twice with 200 μL of washbuffer provided by the kit per well using a magnetic plate washer, thebeads were incubated for 1 hr at RT with 25 μL of the biotin conjugatedantibody solution provided by the kit with shaking. Streptavidinsolution was added for 30 min with shaking at RT. After washing with 200uL wash buffer per well, the beads were resuspended in sheath fluid (150μL) and analyzed immediately. The level of each analyte in thesupernatant was calculated using Xcel Fit software with a 4 or5-parameter equation using each standard curve. The inhibitions of eachcytokine production were calculated at each concentration by comparisonwith vehicle control. The IC₅₀ values were determined fromconcentration-inhibition curves using XL-Fit (idbs, Guildford, UK)

Cytokine Production in Primary Bronchial Epithelial Cells from COPD.

Primary airway epithelial cells obtained from patients with COPD werepurchased from Asterand (Royston, UK), and maintained in bronchialepithelial cell growth media that was prepared by mixing together LHC8(lnvitrogen) (500 mL), with LHC9 (Invitrogen) (500 mL) and 3 μL ofretinoic acid solution (5 mg/mL in neat DMSO. The media was removed byaspiration and fresh BEGM (200 μL) was added to each well. Whereappropriate, 1 μL of a solution of the test compound at the stateconcentrations or 1 μL of DMSO as the vehicle control was added and thecells were incubated for 2 hr. The cells were stimulated with TNFα (50μL; final concentration 50 ng/mL) and then incubated for 4 hr at 37° C.and 5% CO₂. The supernatant was then collected and kept at −20° C.

The levels of IL-6 and IL-8 were determined by ELISA using R&D Systems'Human IL-6 and IL-8 Duoset® Elisa Kits. The inhibition of IL-6 and IL-8production was calculated at each concentration by comparison withvehicle control. The 50% inhibitory concentrations (IC₅₀) weredetermined from the resultant concentration-response curves using XL-Fit(idbs, Guildford, UK).

In Vivo Screening: Pharmacodynamics and Anti-inflammatory Activity

LPS-induced Neutrophil Accumulation in Mice

Non-fasted Balb/c mice were dosed by the intra tracheal route witheither vehicle, or the test substance at the indicated times (within therange 2-8 hr) before stimulation of the inflammatory response byapplication of an LPS challenge. At T=0, mice were placed into anexposure chamber and exposed to LPS (7.0 mL, 0.5 mg/mL solution in PBS)for 30 min). After a further 8 hr the animals were anesthetized, theirtracheas cannulated and BALF extracted by infusing and then withdrawingfrom their lungs 1.0 mL of PBS via the tracheal catheter. Total anddifferential white cell counts in the BALF samples were measured using aNeubaur haemocytometer. Cytospin smears of the BALF samples wereprepared by centrifugation at 200 rpm for 5 min at RT and stained usinga DiffQuik stain system (Dade Behring). Cells were counted using oilimmersion microscopy. Data for neutrophil numbers in BAL are shown asmean ±S.E.M. (standard error of the mean). The percentage inhibition ofneutrophil accumulation was calculated for each treatment relative tovehicle treatment,

Cigarette Smoke Model

A/J mice (males, 5 weeks old) were exposed to cigarette smoke (4%cigarette smoke, diluted with air) for 30 min/day for 11 days using aTobacco Smoke Inhalation Experiment System for small animals (ModelSIS-CS; Sibata Scientific Technology, Tokyo, Japan). Test substanceswere administered intra-nasally (35 μL of solution in 50% DMSO/PBS) oncedaily for 3 days after the final cigarette smoke exposure. At 12 hrafter the last dosing, each of the animals was anesthetized, the tracheacannulated and bronchoalveolar lavage fluid (BALF) was collected. Thenumbers of alveolar macrophages and neutrophils were determined by FACSanalysis (EPICS® ALTRA II, Beckman Coulter, Inc., Fullerton, Calif.,USA) using anti-mouse MOMA2 antibody (macrophage) or anti-mouse 7/4antibody (neutrophil). BALF was centrifuged and the supernatant wascollected. The level of keratinocyte chemoattractant (KC; CXCL1) in BALFwas quantitated using a Quentikine® mouse KC ELISA kit (R&D systems,Inc., Minneapolis, Minn., USA).

Summary of In Vitro and In Vivo Screening Results

The in vitro profile of the compounds of the present invention disclosedherein, as determined using the protocols described above, are presentedbelow (Tables 3a-h) in comparison with a structurally related ReferenceCompound which isN-(4-(4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)pyridin-2-yl)-2-methoxyacetamide,which has been previously described as a potent anti-inflammatory agentwith anti-viral activity (Ito, K. et al., WO 2010/112936,PCT/GB2010/050575, 7 Oct. 2010 and Ito, K, et al., WO 2010/067130,PCT/GB2009/051702, 17 Jun. 2010.

The compounds of the present invention demonstrate a very similarinhibitory profile to the Reference Compound in the range of kinaseenzyme assays with the marked exception of the inhibition the moleculepossess against of the enzyme GSK3α, which is very much weaker than theReference Compound (Table 3a and Table 3b).

TABLE 3a p38 MAPK and GSK3α Enzyme Profile of Compound Examples TestCompound IC50 Values for Enzyme Inhibition (nM) Example No. p38 MAPKαp38 MAPKγ GSK3α Reference 12 344 45 Compound 1 60 3739 >17000 2 164557 >1670 3 173 1503 2494 4 165 8198 >16600 5 161 >16300 >16300 6161 >16200 >16200 7 170 1702 3505 8 151 >15500 >15500 9 171 760 3260 10195 >16300 >16300 11 356 >16730 >16700 12 169 >16700 >16730 13262 >16200 >16200 14 119 >16300 >16300 15 155 >16600 >16600 16616 >16200 >16200 17 83 >16300 >16300 18 133 >15800 >15800 1998 >15100 >15100 20 9 >16000 >16000 21 33 >1670 >1670 22 281 >1590 >159023 212 >1660 >1660 24 36 695 >1590 25 77 281 >1590 26 549 >1630 >1630 27105 535 2108 28 1422 >1540 >1540 29 311 423 >1620 30 68 >1620 >1620 31118 >1580 >1580 32 189 >1620 >1620 33 60 264 2377

TABLE 3b c-Src and Syk Enzyme Profile of Compound (I) IC₅₀ Values forEnzyme Inhibition (nM) Test Compound c-Src Syk Example 1 22 334Reference 5 42 Compound

The kinase binding profile of Example 1 of the present invention wasalso compared with the Reference Compound against p38 MAPK, HCK, cSrc,Syk, and GSK3α/β. Example 1 displayed a very different phenotype,demonstrating profound inhibition of binding versus p38MAPK, HCK, cSrcand Syk kinases, without significant effect against GSK3α (Table 3c).

TABLE 3c Comparison of the Enzyme Binding Profile of Compound (I) withthe Reference Compound. Test Kd value for kinase binding (nM) Com- p38p38 pound MAPKα MAPKγ HCK cSrc Syk GSK3α GSK3β Example 1 20 43 8 10 1420000 1200 Reference 1 5 5 4 9 180 24 compound

The compounds of the present invention demonstrate a similar profile tothe Reference Compound in cellular assays that reveal anti-inflammatoryproperties against endotoxin mediated release of both TNFα and IL-8(Table 3d). The profiles of the compounds are also similar in cellularsystems measuring their effects on respiratory virus replication (HRVinduced ICAM1 and CPE expression and RSV stimulated expression ofF-protein) as well as virus-induced inflammation (HRV evoked release ofIL-8) (Table 3e and Table 3f).

TABLE 3d Inhibition of LPS induced TNFα and IL-8 Release and PolyICinduced ICAM-1 Expression for Compound Examples LPS Induced Release (nM)PolyIC/ TNFα IL-8 ICAM1 (nM) Test Compound IC₅₀ REC₅₀ IC₅₀ IC₅₀ ExampleNo. (THP1) (dU937) (dU937) (BEAS2B) Reference 13 0.13 1.3 2.1 Compound 13.4 2.3 2.2 10 2 2.8 2.4 2.7 4.3 3 1.2 1.7 1.8 4.1 4 4.6 3.1 2.3 144 566 2.9 6.2 17 6 225 7.0 15 56 7 10 1.7 2.1 23 8 225 227 235 22 9 1.3 1.72.2 3.0 10 45 15 15 43 11 21 35 >1675 11 12 30 2.0 2.4 2.7 131603 >1618 >1618 3.0 14 2.7 2.0 1.6 9.8 15 3.0 2.2 2.3 9.3 16 4.1 1.10.31 36 17 4.3 2.0 2.1 6.7 18 157 13 15 28 19 192 13 14 43 20 121 18 2316 21 17. 9.7 >1677 36 22 30 17 >1592 13 23 24 8.0 22 4.2 24 0.8 2.3 865.0 25 0.4 0.84 1.5 2.5 26 1.9 4.1 6.6 8.4 27 0.5 0.54 2.0 1.6 28 0.4 1418 3.0 29 1.6 11 2.3 2.8 30 1.6 1 3.0 11 31 6.1 16 32 80 32 14 12 9.7 2133 0.5 7.4 6.3 2.6

TABLE 3e The Effect of Compound Examples on HRV-16 propagation(expression of ICAM-1 and CPE) and Inflammation (IL-8 release) and onRSV propagation (F-protein expression). IC₅₀ Values (nM) and/or %inhibition at 0.04 μg/mL Test Compound HRV IL-8 HRV CPE RSV (F-Elisa)Example No. (BEAS2B) (MRC5) (HBEC) Reference 0.065 4.7 22.0 Compound 10.036 17.1 (57%) 15.4 (85%) 2 100%  5% 42% 3 100% 100%  NT 4 100% 44% NT5  49% 91% NT 6  77% 46% NT 7 100% NE NT 8 100% 100%  NT 9 100% 100%  NT10 100% 100%  NT 11 100% 100%  NT 12 100% 100%  NT 13 100% 100%  NT 14100% 100%  NT 15 100% 100%  NT 16 100% 10% NT 17 100% NE NT 18 100% NENT 19 100% NE NT 20 100% NE NT 21 100%  3% 66% 22 100% 48% 78% 23 100%18% 41% 24 100% 41% NT 25 100%  33%* NT 26 100% 69% NT 27 100% 51% NT 28100% 54% NT 29 100% 13% NT 30 100% NE NT 31 100% NE NT 32 100% 26% NT 33100% 44% NT NE: no effect, ≤0% at 0.04 μg/mL; *tested at 0.0008 μg/mL,low cell viability at 0.04 μg/mL; NT: not tested

TABLE 3f The Effect of Example 1 on Inflammation (Expression of ICAM-1)IC₅₀ Values (nM) for HRV Stimulated Release/Expression Test SubstanceICAM1 (BEAS2B) Example 1 0.023 Reference Compound 0.37

Example 1 of the present invention demonstrated higher efficacy inpro-inflammatory cytokine production in sputum macrophage and bronchialepithelial cells obtained from COPD patients, which were largelyinsensitive to fluticasone propionate, a corticosteroid, (Table 3g).

TABLE 3g The Effect of Example 1 and Fluticasone propionate onpro-inflammatory cytokine release in sputum macrophages and bronchialepithelial cell from COPD patients. IC₅₀ values (nM) and/or E max (% inparentheses)¹ for Test Substance Indicated Fluticasone Cells TypeCytokine Example 1 Propionate IL-6 43 (79) (26) Sputum IL-8 68 (64) (19)Macrophage {open oversize brace} TNFα 17 (86) (18) MIP1α 7.5 (89) (20)Bronchial IL-6 1.7 (100) (38) {open oversize brace} Epithelial Cell IL-80.85 (100) (17) ¹E-max values (maximum inhibiton) were calculated as the% inhibition obtained at 0.1 μg/mL

However, advantageously, the compounds of the present invention showmarkedly less activity in assay systems that measure its impact on cellviability and cell division (mitosis) indicating that the compound islikely to possess a superior therapeutic index over the ReferenceCompound (Table 3h).

TABLE 3h Effect of Compound Examples on Cellular Viability and CellDivision MTT Assay¹ Mitosis Assay Cell viability at time point %inhibition in PBMC Test Compound in d-U937 Cells Cells at concn ExampleNo. 4 h 24 h 1 μg/mL 5 μg/mL Reference −ve +ve NT 87.8 Compound 1 −ve−ve 13.7 31.3 2 −ve −ve NT 70.6 3 −ve −ve NT NT 4 −ve −ve NT NT 5 −ve−ve NT NT 6 −ve −ve NT NT 7 −ve −ve NT 10.2 8 −ve −ve 15.6 NT 9 −ve −veNT 50.3 10 −ve −ve NT NT 11 −ve −ve NT NT 12 −ve −ve NT NT 13 −ve −ve NTNT 14 −ve −ve NT NT 15 −ve −ve NT NT 16 −ve −ve NT NT 17 −ve −ve NT NT18 −ve −ve NT NT 19 −ve −ve n.t. NT 20 −ve −ve NT NT 21 −ve −ve NT NT 22−ve −ve NT 70.8 23 −ve −ve NT NT 24 −ve −ve NT NT 25 −ve −ve 29.1 63.526 −ve −ve NT NT 27 +ve −ve NT 11.2 28 −ve −ve NT NT 29 +ve −ve NT NT 30−ve −ve NT NT 31 −ve −ve NT NT 32 −ve −ve NT 33.0 33 −ve −ve NT 67.2¹Cell viability screen: −ve and +ve indicate the value is below andabove respectively, the no significant effect threshold defined as 30%inhibition at 1 μg/mL at the time point indicated; NT: not tested

Treatment of mice with Example 1 was found to produce a dose dependentinhibition on LPS-induced neutrophil accumulation and a time courseexperiment revealed that the drug substance had a long duration ofaction (Table 4)

TABLE 4 The Effects of Treatment with Example 1 on LPS-Induced AirwayNeutrophilia in Mice. Neutrophil numbers in BALF (×10⁵/mL) Example 1 atpre-dose time indicated (% inhibition)¹ (mg/mL) 2 hr 8 hr 12 hr Vehicle18.9 ± 2.5     — — 0.05 15.6 ± 2.1 (18)  — — 0.2 9.8 ± 1.6 (48) — — 1.0 4.4 ± 0.89 (77) 9.9 ± 1.8 (48) 18.3 ± 2.3 (4) ¹N = 8 per group

The result of treatment with Example 1 on macrophage and neutrophilaccumulation in BALF in the mouse cigarette smoke model was investigated(Table 5). The cigarette smoke model used for this study is reported tobe a corticosteroid refractory system, (Medicherla S. et al., J.Pharmacol. Exp. Ther., 2008, 324(3):921-9.) and it was confirmed thatfluticasone propionate did not inhibit either neutrophil or macrophageaccumulation into airways at 1.75 μg/mouse (35 μL, bid, i.n.), the samedose that produced >80% inhibition of LPS-induced neutrophilaccumulation.

Treatment of mice with Example 1 was found to produce a dose-dependentinhibition on both macrophage and neutrophil accumulation in BALFinduced by cigarette smoke.

TABLE 5 The Effects of Treatment with Example 1 on Tobacco Smoke inMice. Cell numbers in BALF ×10⁴/mL Treatment (% inhibition) Example 1(μg/mL) Macrophage Neutrophil Vehicle + Air 4.3 ± 0.45    2.6 ± 0.21   Vehicle + Tobacco Smoke 14.4 ± 0.33    13.7 ± 0.31    0.32 13.3 ± 0.20(11) 12.4 ± 0.32 (12) 1.6 11.6 ± 0.42 (28) 10.5 ± 0.06 (29) 8.0 10.1 ±0.42 (43)  9.1 ± 0.28 (41) 40  7.9 ± 0.20 (64)  7.9 ± 0.34 (52) The datafor cell numbers are shown as the mean ± SEM, N = 5

Treatment of mice with Example 1 also inhibited cigarette smoke inducedCXCL1 (KC) production in BALF in a dose-dependent manner (Table 6).

TABLE 6 The Effects of Treatment with Example 1 on CXCL1 (KC) release inBALF on Tobacco Smoke in Mice. Treatment CXCL1 in BALF Example 1 (μg/mL)pg/mL (% inhibition) Vehicle + Air 8.2 ± 0.30    Vehicle + Tobacco Smoke13.6 ± 1.89    0.32 13.6 ± 1.69 (0)  1.6 12.2 ± 0.96 (26) 8.0 11.4 ±0.15 (41) 40  9.5 ± 0.84 (76) The data for CXCL level are shown as themean ± SEM, N = 5

In summary, these results suggest that compounds of the presentinvention have similar anti-inflammatory properties to the ReferenceCompound disclosed supra and, advantageously, are associated with ahigher therapeutic index.

Formulation Example Preparation of Pharmaceutical Formulations

An exemplary pharmaceutical formulation of the invention would consistof 0.4 wt. % of Example 1 (as the anhydrous free base in solidcrystalline form), 98.6 wt. % lactose monohydrate (inhalation grade) and1.0 wt. % magnesium stearate, wherein the wt. % of all components isbased on the weight of the dry pharmaceutical formulation.

Throughout the specification and the claims which follow, unless thecontext requires otherwise, the word ‘comprise’, and variations such as‘comprises’ and ‘comprising’, will be understood to imply the inclusionof a stated integer, step, group of integers or group of steps but notto the exclusion of any other integer, step, group of integers or groupof steps.

All patents and patent applications referred to herein are incorporatedby reference in their entirety.

The invention claimed is:
 1. A dry powder pharmaceutical formulation forinhalation comprising: (i) a compound of formula (I)

wherein: R¹ represents C₁₋₁₀ alkyl, C₃₋₁₀ cycloalkyl or halo substitutedC₁₋₁₀ alkyl, R² represents hydrogen, hydroxyl, halogen, C₁₋₆ alkyl orC₁₋₆ alkoxy, R³ represents phenyl optionally substituted by 1 to 3substituents independently selected from hydroxyl, halogen, C₁₋₆ alkyl,and C₁₋₆ alkoxy, or a pharmaceutically acceptable salt thereof,including all stereoisomers and tautomers thereof; and (ii) anexcipient.
 2. A dry powder pharmaceutical formulation according to claim1, wherein R¹ represents t-butyl.
 3. A dry powder pharmaceuticalformulation according to claim 1, wherein R² is a meta or parasubstituent.
 4. A dry powder pharmaceutical formulation according toclaim 1, wherein R² represents hydrogen, methyl, methoxy or hydroxyl. 5.A dry powder pharmaceutical formulation according to claim 1, wherein R³represents unsubstituted phenyl.
 6. A dry powder pharmaceuticalformulation according to claim 1, wherein R³ represents phenyl bearingone to three substituents independently selected from methyl, ethyl,isopropyl, hydroxyl, methoxy, fluoro or chloro.
 7. A dry powderpharmaceutical formulation according to claim 1, wherein the phenyl ofR³ either has hydrogen in the para position or when it bears asubstituent in the para position said substituent is selected frommethyl, hydroxyl, methoxy, fluoro or chloro.
 8. A dry powder formulationaccording to claim 1, wherein the compound of formula (I) is in its freebase form.
 9. A dry powder formulation according to claim 1, wherein thecompound of formula (I) is in solid crystalline form.
 10. A dry powderformulation according to claim 9, wherein the compound of formula (I) isin anhydrous form.
 11. A dry powder formulation according to claim 1further comprising magnesium stearate.
 12. A dry powder formulationaccording to claim 1, wherein the compound of formula (I) is selectedfrom the group consisting of:1-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-(2-(phenylamino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;1-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((3-hydroxyphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;1-(3-(tert-butyl)-1-(4-hydroxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2-(phenylamino)pyrimidin-4-yl)oxy)naphthalen-1-y)urea;1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((2-fluorophenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((2-methoxyphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2((2-chlorophenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;1-(3-(tert-butyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2-(phenylamino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((2,4-dimethoxyphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((4-hydroxypheny)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((2,5-dimethylphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-(p-tolylamino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-(m-tolylamino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((3-chlorophenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((3-methoxyphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((3-fluorophenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((4-chlorophenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((4-methoxyphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((4-chloro-2-methylphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((2-chlorophenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2(2-isopropylphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-(o-tolylamino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((4-ethoxyphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-(4-fluorophenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazo1-5-yl)-3-(4-((2-((4-hydroxy-2-methylphenyl)amino)pyrimidin-4-yl)poxy)naphthalen-1-yl)urea;1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((4-hydroxy-3-methoxyphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((3-hydroxy-4-methylphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((3,4-dimethoxyphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((3-chloro-4-methoxyphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-(3-fluoro-4-hydroxyphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((2-fluoro-4-hydroxyphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2((2-chloro-4-hydroxyphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((2,4-dihydroxyphenyl)amino)pyrimidin-4-yl)poxy)naphthalen-1-yl)urea;and1-(3-(tert-butyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((4-hydroxyphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea; and pharmaceuticallyacceptable salts of any one thereof, including all stereoisomers andtautomers thereof.
 13. A method of treating respiratory viral infectionin a subject with a chronic condition selected from the group consistingof congestive heart failure, diabetes, cancer and immunosuppression,said method comprising administering to the subject by topicaladministration to the lung an effective amount of a dry powderpharmaceutical formulation according to claim
 1. 14. A method oftreatment of a condition selected from COPD, asthma, paediatric asthma,cystic fibrosis, sarcoidosis, idiopathic pulmonary fibrosis, rhinitis,sinusitis, conjunctivitis, allergic dermatitis, contact dermatitis,psoriasis, ulcerative colitis, inflamed joints secondary to rheumatoidarthritis or osteoarthritis, rheumatoid arthritis, pancreatitis,cachexia, inhibition of the growth and metastasis of tumours, gastriccarcinoma, colorectal carcinomas and malignant melanoma which comprisesadministering to a subject by topical administration to the lung aneffective amount of a dry powder pharmaceutical formulation according toclaim
 1. 15. The method of claim 14, wherein the condition is COPD andis selected from chronic bronchitis and emphysema.
 16. The method ofclaim 14, wherein the rhinitis is allergic rhinitis.
 17. The method ofclaim 14, wherein the conjunctivitis is allergic conjunctivitis.
 18. Themethod of claim 14, wherein the metastasis of tumours is selected fromnon-small cell lung carcinoma and breast carcinoma.
 19. The dry powderpharmaceutical formulation according to claim 3, wherein R² is a parasubstituent.